Imidazo[1,5-a] pyridine derivatives, method for preparing same and pharmaceutical compositions containing same

ABSTRACT

The invention concerns compounds of formula I, a method for preparing said compounds, pharmaceutical compositions containing same and the therapeutic uses thereof.

This is a continuation of PCT application PCT/FR2006/000567 filed onMar. 15, 2006.

A subject matter of the present invention is novelimidazo[1,5-a]pyridine derivatives which are inhibitors of FGFs(fibroblast growth factor), their process of preparation and thepharmaceutical compositions comprising them.

FGFs are a family of polypeptides synthesized by a large number of cellsduring embryonic development and by cells of adult tissues in variouspathological conditions.

Certain derivatives of naphthyridinediamines and corresponding ureaswhich are selective inhibitors of FGF-1 are known (Batley B. et al.,Life Sciences, (1998), Vol. 62, No. 2, pp. 143-150; Thompson A. et al.,J. Med. Chem., (2000), Vol. 43, pp. 4200-4211).

Indolizine derivatives which are antagonists of the binding of FGFs totheir receptors are described in international patent applications WO03/084956 and WO 2005/028476.

It has now been found that compounds which are imidazo[1,5-a]pyridinederivatives exhibit a powerful antagonist activity for the binding ofFGFs to their receptors as well as a very good activity in vivo. This isbecause, surprisingly, in vivo models in the mouse, the dose of 10 mg/kgallows us to obtain a maximum activity of the compounds. This effect wasonly obtained at the dose of 50 mg/kg with the indolizine seriesdescribed in international patent applications WO 03/084956 and WO2005/028476.

Thus, a subject matter of the present invention is novelimidazo[1,5-a]pyridine derivatives of formula I:

in which:

-   -   R, present on the 5, 6, 7 or 8 positions of the        imidazo[1,5-a]pyridine, represents a hydrogen atom, a halogen        atom, an alkyl radical of 1 to 5 carbon atoms, a hydroxyl        radical, an alkoxy radical of 1 to 5 carbon atoms, a —COOR₆        radical or a radical of formula:        -   —NR₄R₅        -   —NH—SO₂-Alk        -   —NH—CO-Alk        -   —NR₆—CO₂-Alk        -   —O-Alk-COOR₆        -   —O-Alk-NR₄R₅        -   —O—(CH₂)-Ph        -   —CO—NR₄R₅, or        -   —CO—NH—CH(R₇)—(CH₂)_(m)—COOR₆        -   in which:            -   Alk represents an alkyl radical or an alkylene radical                of 1 to 5 carbon atoms,            -   n represents an integer from 1 to 5,            -   m represents an integer from 0 to 4,            -   R₄ and R₅ represent, independently of one another, a                hydrogen atom, an alkyl radical of 1 to 5 carbon atoms                or a benzyl radical,            -   R₆ represents a hydrogen atom or an alkyl radical of 1                to 5 carbon atoms,            -   R₇ represents a hydrogen atom, an alkyl radical of 1 to                5 carbon atoms or a radical of formula:                -   -Alk-CONR₄R₅                -   -Alk-OR₆                -   -Alk-NR₄R₅                -   -Ph, or                -   —CH₂Ph, and            -   Ph represents a phenyl radical optionally substituted by                one or more groups chosen from halogen atoms, alkoxy                radicals of 1 to 5 carbon atoms and —COOR₆ radicals                where R₆ is as defined above;    -   R₁ represents a hydrogen atom, a halogen atom, a cyano radical,        a —COOR₆ radical or a radical of formula:        -   —NR₄R₅        -   —NH—SO₂-Alk        -   —NH—CO—CF₃        -   —NH—CO-Ph        -   —NH—CO-Alk        -   —NH—CO₂-Alk        -   —CONR₄R₅        -   a phenyl radical optionally substituted by one or more            groups chosen from halogen atoms, alkyl radicals of 1 to 5            carbon atoms, alkoxy radicals of 1 to 5 carbon atoms and            —COOR₆ radicals,        -   a 5-membered heteroaryl radical comprising a heteroatom            chosen from a sulfur atom, an oxygen atom or a nitrogen atom            and optionally comprising a second nitrogen atom, said            heteroaryl optionally being substituted by one or more            groups chosen from halogen atoms, alkyl radicals of 1 to 5            carbon atoms, alkoxy radicals of 1 to 5 carbon atoms and            —COOR₆ radicals, or        -   a 6-membered heteroaryl radical comprising 1 or 2 nitrogen            atoms and optionally being substituted by one or more groups            chosen from halogen atoms, alkyl radicals of 1 to 5 carbon            atoms, alkoxy radicals of 1 to 5 carbon atoms and —COOR₆            radicals,        -   in which Alk, Ph, R₄, R₅ and R₆ are as defined as above;    -   R₂ and R₃ represent, independently of one another, a hydroxyl        radical, an alkoxy radical of 1 to 5 carbon atoms, an amino        radical, a —COOR₆ radical, a nitro radical or a radical of        formula:        -   —NR₄R₅        -   —NH—CO-Alk        -   —NH—CO-Ph        -   —NH—CO₂-Alk        -   —NH—SO₂-Alk        -   —CO—NR₄R₅, or        -   —CO—NHOH        -   in which Alk, Ph, R₄, R₅ and R₆ are as defined as above;            or else R₂ and R₃ together form, with the carbon atoms of            the phenyl ring to which they are attached, a 6-membered            carbon ring comprising a nitrogen atom and another            heteroatom, such as oxygen.

The compounds of formula I can exist in the form of bases or salified byacids or bases, in particular pharmaceutically acceptable acids orbases. Such addition salts also form part of the invention.

The compounds according to the invention can also exist in the form ofhydrates or solvates, namely in the form of associations or combinationswith one or more molecules of water or with a solvent. Such hydrates andsolvates also form part of the invention.

Within the context of the present invention:

-   -   the term “an alkyl radical” is understood to mean: a saturated,        linear or branched, aliphatic radical which can comprise from 1        to 5 carbon atoms. Mention may be made, by way of example, of        the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,        tert-butyl and 2,2-dimethylpropyl radicals;    -   the term “an alkylene radical” is understood to mean: an alkyl        radical as defined above which is saturated and linear or        branched and which is divalent. Mention may be made, by way of        example, of the methylene, ethylene and propylene radicals;    -   the term “an alkoxy radical” is understood to mean: an —O-alkyl        radical where the alkyl group is as defined above and can        comprise from 1 to 5 carbon atoms. Mention may be made, by way        of example, of the methoxy, ethoxy and propoxy radicals;    -   the term “a halogen atom” is understood to mean: a fluorine, a        chlorine, a bromine or an iodine;    -   the term “a heteroatom” is understood to mean: a nitrogen,        oxygen or sulfur atom;    -   the term “a 5-membered heteroaryl radical” is understood to        mean: an aromatic cyclic radical comprising 5 ring members and        comprising a heteroatom as defined above and optionally also a        second heteroatom, which is a nitrogen atom, said aromatic        radical optionally being substituted. Mention may be made, by        way of example, of a thienyl, furyl and pyrrolyl radical; and    -   the term “a 6-membered heteroaryl radical” is understood to        mean: an optionally substituted aromatic cyclic radical        comprising 6 ring members and comprising 1 or 2 nitrogen atoms.        Mention may be made, by way of example, of a pyridinyl radical.

Mention may be made, among the compounds which are subject matters ofthe invention, of a second group of compounds of formula I in which:

-   -   R, present on the 6, 7 or 8 positions of the        imidazo[1,5-a]pyridine, represents a hydrogen atom, an alkyl        radical of 1 to 5 carbon atoms, an alkoxy radical of 1 to 5        carbon atoms, a hydroxyl radical, a —COOR₆ radical or a radical        of formula:        -   —NR₄R₅        -   —NH—SO₂-Alk        -   —NH—CO-Alk        -   —NR₆—CO₂-Alk        -   —O-Alk-COOR₆        -   —O-Alk-NR₄R₅        -   —O—CH₂-Ph        -   —CO—NR₄R₅, or        -   —CO—NH—CH(R₇)—(CH₂)_(m)—COOR₆

-   in which Alk, Ph, R₄, R₅, R₆, R₇ and m are as defined as above;    -   R₁ represents a hydrogen atom, a halogen atom, a cyano radical,        a —COOR₆ radical or a radical of formula:        -   —NR₄R₅        -   —NH—SO₂-Alk        -   —NH—CO—CF₃        -   —NH—CO-Ph        -   —NH—CO-Alk        -   —CO—NR₄R₅        -   a phenyl radical optionally substituted by one or two groups            chosen from halogen atoms, alkoxy radicals of 1 to 5 carbon            atoms and —COOR₆ radicals;        -   a 5-membered heteroaryl radical comprising a heteroatom            chosen from a sulfur atom, an oxygen atom or a nitrogen atom            and optionally comprising a second nitrogen atom, said            heteroaryl optionally being substituted by one or two groups            chosen from halogen atoms, alkyl radicals of 1 to 5 carbon            atoms, alkoxy radicals of 1 to 5 carbon atoms and —COOR₆            radicals, or        -   a 6-membered heteroaryl radical comprising 1 or 2 nitrogen            atoms and optionally being substituted by one or two groups            chosen from halogen atoms, alkyl radicals of 1 to 5 carbon            atoms, alkoxy radicals of 1 to 5 carbon atoms and —COOR₆            radicals,

-   where Alk, Ph and R₆ are as defined as above;    -   R₂ and R₃ represent, independently of one another, an alkoxy        radical of 1 to 5 carbon atoms, a —COOR₆ radical, an amino        radical, a nitro radical or a radical of formula:        -   —NR₄R₅        -   —NH—CO-Alk        -   —NH—CO-Ph        -   —NH—SO₂-Alk        -   in which Alk, Ph, R₄, R₅ and R₆ are as defined as above.

Mention may in particular be made, among this second group of compoundsaccording to the invention, of those in which R₇ represents a hydrogenatom, an alkyl radical of 1 to 5 carbon atoms or a radical of formula-Alk-OR₆ or —CH₂-Ph.

Mention may also be made, among this second group of compounds accordingto the invention, of those in which m=0 or 1.

Mention may be made, among the compounds which are subject matters ofthe invention, of a third group of compounds of formula I in which:

-   -   R, present on the 6, 7 or 8 positions of the        imidazo[1,5-a]pyridine, represents a hydrogen atom, an alkoxy        radical of 1 to 5 carbon atoms, a hydroxyl radical, a —COOR₆        radical or a radical of formula:        -   —NR₄R₅        -   —NH—SO₂-Alk        -   —NH—CO-Alk        -   —NR₆—CO₂-Alk        -   —O-Alk-COOR₆        -   —CO—NR₄R₅, or        -   —CO—NH—CH(R₇)— (CH₂)_(m)—COOR₆        -   in which m represents 0 or 1, R₇ represents a hydrogen atom,            an alkyl radical of 1 to 5 carbon atoms or a radical of            formula -Alk-OR₆ or —CH₂-Ph, and Alk, R₄, R₅ and R₆ are as            defined as above;    -   R₁ represents a hydrogen atom, a halogen atom, a cyano radical,        a —COOR₆ radical or a radical of formula:        -   —NR₄R₅        -   —NH—SO₂-Alk        -   —NH—CO-Ph        -   —NH—CO-Alk        -   a phenyl radical optionally substituted by one or two groups            chosen from halogen atoms, alkoxy radicals of 1 to 5 carbon            atoms and —COOR₆ radicals,        -   a heteroaryl radical chosen from thienyl, furyl and pyrrolyl            radicals, said heteroaryl optionally being substituted by            one or two groups chosen from alkoxy radicals of 1 to 5            carbon atoms and —COOR₆ radicals, or        -   a pyridinyl radical optionally substituted by one or two            groups chosen from alkoxy radicals of 1 to 5 carbon atoms            and —COOR₆ radicals,

-   in which Alk, Ph, R₄ and R₆ are as defined as above;    -   R₂ and R₃ represent, independently of one another, an alkoxy        radical of 1 to 5 carbon atoms, a —COOR₆ radical, a nitro        radical, an amino radical or a radical of formula —NH—CO-Alk,        —NH—CO-Ph or —NH—SO₂Alk;        -   in which Alk, Ph and R₆ are as defined as above.

Mention may in particular be made, among all the compounds of formula Iaccording to the invention as defined above, of those in which R₂represents an alkoxy radical of 1 to 5 carbon atoms or a —COOR₆ radicalwhere R₆ is as defined as above.

Mention may also be made, among all the compounds of formula I accordingto the invention as defined above, of those in which R₃ represents anitro radical, an amino radical or a radical of formula —NH—CO-Alk,—NH—CO-Ph or —NH—SO₂Alk, where Alk and Ph are as defined as above.Advantageously, R₃ represents an amino radical.

Mention may be made, among the compounds which are subject matters ofthe invention, of a fourth group of compounds of formula I in which:

-   -   R, present on the 6, 7 or 8 positions of the        imidazo[1,5-a]pyridine, represents a hydrogen atom, a hydroxyl        radical, a —COOR₆ radical or a radical of formula:        -   —O-Alk-COOR₆        -   —CO—NR₄R₅, or        -   —CO—NH—CH(R₇)—COOR₆        -   in which R₇ represents a hydrogen atom, an alkyl radical of            1 to 5 carbon atoms or a radical of formula -Alk-OR₆ and            Alk, R₄, R₅ and R₆ are as defined as above;    -   R₁ represents a hydrogen atom, a halogen atom, a —COOR₆ radical        or a radical of formula:        -   —NH—CO-Ph        -   a phenyl radical optionally substituted by one or two groups            chosen from halogen atoms, alkoxy radicals of 1 to 5 carbon            atoms and —COOR₆ radicals or        -   a thienyl radical optionally substituted by one or two            groups chosen from alkoxy radicals of 1 to 5 carbon atoms            and —COOR₆ radicals,        -   in which Ph and R₆ are as defined as above;    -   R₂ represents an alkoxy radical of 1 to 5 carbon atoms or a        —COOR₆ radical where R₆ is as defined as above; and    -   R₃ represents an amino radical.

Mention may in particular be made, among the compounds which are subjectmatters of the invention, of the following compounds:

-   2-amino-5-{(imidazo[1,5-a]pyridin-3-yl)carbonyl}benzoic acid;-   2-amino-5-{[1-(4-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl]carbonyl}benzoic    acid;-   2-amino-5-{[1-(3-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl]carbonyl}benzoic    acid;-   (4-amino-3-methoxyphenyl)(1-bromoimidazo[1,5-a]pyridin-3-yl)methanone;-   3-(4-amino-3-methoxybenzoyl)imidazo[1,5-a]pyridine-8-carboxylic    acid;-   5-[3-(4-amino-3-methoxybenzoyl)imidazo[1,5-a]pyridin-1-yl]thiophene-2-carboxylic    acid;-   -3-(4-amino-3-methoxybenzoyl)imidazo[1,5-a]pyridine-1-carboxylic    acid;-   N-[3-(4-amino-3-methoxybenzoyl)imidazo[1,5-a]pyridin-1-yl]-3-methoxybenzamide;-   3-(4-amino-3-methoxybenzoyl)imidazo[1,5-a]pyridine-6-carboxylic    acid;-   3-(4-amino-3-methoxybenzoyl)imidazo[1,5-a]pyridine-7-carboxylic    acid;-   3-[3-(4-amino-3-methoxybenzoyl)imidazo[1,5-a]pyridin-1-yl]benzoic    acid;-   (4-amino-3-methoxyphenyl)[1-(3-fluorophenyl)imidazo-[1,5-a]pyridin-3-yl]methanone-   3-{3-(4-amino-3-methoxybenzoyl)-7-[(methylamino)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoic    acid;-   (4-amino-3-methoxyphenyl)(8-hydroxyimidazo[1,5-a]pyridin-3-yl)methanone;-   (4-amino-3-methoxyphenyl)(7-hydroxyimidazo[1,5-a]pyridin-3-yl)methanone;-   {[3-(4-amino-3-methoxybenzoyl)imidazo[1,5-a]pyridin-7-yl]oxy]acetic    acid;-   3-(4-amino-3-methoxybenzoyl)-1-(3-methoxyphenyl)imidazo[1,5-a]pyridine-7-carboxylic    acid;-   methyl    N-{[3-(4-amino-3-methoxybenzoyl)imidazo[1,5-a]pyridin-7-yl]carbonyl}-D-alaninate;-   N-{[3-(4-amino-3-methoxybenzoyl)imidazo[1,5-a]pyridin-6-yl]carbonyl}-L-serine.

In that which follows, depending on the meanings of the varioussubstitutions R, R₁, R₂ and R₃, the compounds of formula I will becalled Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Is, Im, In, Io, Ip,Iq, Ir, It, Iu, Iv, Iw, Ix, Iy, Iz and Iz′.

The present invention also relates to a process for the preparation ofthe compounds of formula I, characterized in that:

-   A) the compound of formula II:

-   in which R is as defined for the compound of formula I but R is    other than a radical capable of reacting with the compounds of    formula III, such as a hydroxyl radical, a carboxyl radical or an    —NR₄R₅ radical, and R is other than an —NH—CO₂R₆ radical or than a    —CONR₄R₅ radical, R₁ advantageously representing a hydrogen atom, is    condensed with the compound of formula III:

-   in which X represents a halogen atom and R₂ and R₃ represent,    independently of one another, an alkoxy radical of 1 to 5 carbon    atoms, a nitro radical or a —COOR₆ radical where R₆ represents an    alkyl radical of 1 to 5 carbon atoms, in order to obtain:    -   the compounds of formula Ia, which are compounds of formula I in        which R₂ or R₃ represents a nitro radical, or    -   the compounds of formula Ib, which are compounds of formula I in        which R₂ or R₃ represents a —COOR₆ radical where R₆ represents        an alkyl radical of 1 to 5 carbon atoms,-   and, subsequently:-   a) the compounds of formula Ia are subjected to a reduction    reaction, in order to obtain the compounds of formula Id:

-   in which R and R₁ are as defined for the compound of formula Ia and    R₂ or R₃ represents an amino radical;-   the compounds of formula Id can subsequently be subjected to an    alkylation, acylation or sulfonylation reaction in order to obtain    the compounds of formula Ig:

-   in which R and R₁ are as defined for the compound of formula Id and    R₂ or R₃ represents an —NR₄R₅, —NHCOAlk, —NHCO₂Alk or —NHSO₂Alk    radical;-   b) or the compounds of formula Ib are subjected to a saponification    reaction in order to obtain the compounds of formula Ie:

-   in which R and R₁ are as defined for the compound of formula Ib and    R₂ or R₃ represents a carboxyl radical,-   the compounds of formula Ie can subsequently be subjected to a    coupling reaction after activation of the carboxyl functional group    with, for example, the reactant BOP    [benzotriazol-1-yloxytris(dimethylamino)phosphonium    hexafluorophosphate] in the presence of a base, such as    triethylamine, according to the procedure described in Tetrahedron    Letters, (1975), 14, 1219-1222, and then addition of an amine of    formula HNR₄R₅ or of hydroxylamine in order to obtain the compounds    of formula Ih:

-   in which R and R₁ are as defined for the compounds of formula Ie and    R₂ or R₃ represents a —CONR₄R₅ or —CONHOH radical;-   OR-   B) the compound of formula II as defined above in part A) is    condensed with the compound of formula III′:

-   in which X represents a halogen atom and R₂′ and R₃′ together form,    with the carbon atoms of the phenyl ring to which they are attached,    a 6-membered carbon ring comprising a nitrogen atom and another    heteroatom, such as oxygen,-   in order to obtain the compounds of formula Ic:

-   in which R and R₁ are as defined for the compound of formula II,-   said compounds of formula Ic subsequently being subjected to an    alcoholysis reaction in order to give the compounds of following    formula If:

-   in which R and R₁ are as defined for the compound of formula II and    R₆ is as defined for the compound of formula I,-   the compounds If can subsequently be saponified in order to obtain    the compounds of formulae Id or Ie in which R and R₁ are as defined    for the compounds of formula II, R₂ represents a —COOH radical and    R₃ represents an —NH₂ radical;-   OR-   C) the compound of formula I in which R₁ represents a hydrogen atom,    as obtained above in part A), is subjected to a bromination reaction    in order to obtain the compounds of formula Ii:

-   in which R, R₂ and R₃ are as defined for the compound of formula I    (when R₂ and R₃ do not together form a heteroaryl) and R₁ represents    a bromine atom, the compounds of formula Ii for which R is other    than a bromine atom or than an iodine atom can subsequently be    subjected, in the presence of a palladium catalyst, of a ligand and    of a base:-   a) either to an imination reaction with a benzophenone imine    according to the reaction conditions described in Tetrahedron,    (2003), 59(22), 3925-3936, followed by an acid hydrolysis reaction,    in order to obtain the compounds of formula Ij:

-   in which R, R₂ and R₃ are as defined for the compounds of formula Ii    and R₁ represents an —NH₂ radical,-   b) or to a cyanation reaction with zinc cyanide according to the    reaction conditions described in J. Med. Chem., (2003), 46, 265-283,    in order to obtain the compounds of formula Ik:

-   in which R, R₂ and R₃ are as defined for the compounds of formula Ii    and R₁ represents a —CN radical,    -   the compounds of formula Ik can subsequently be subjected to a        basic hydrolysis reaction in order to obtain the compounds of        formula Im:

-   in which R, R₂ and R₃ are as defined for the compounds of formula Ik    and R₁ represents a —CONH₂ radical,    -   or alternatively the compounds of formula Ik are subjected to a        Pinner reaction [The Chemistry of Amidines and Imidates; edited        by S. Patai, J. Wiley and Sons, New York, (1975), 385-489] with        a primary alcohol, such as methanol or ethanol, in the presence        of hydrogen chloride gas to result in the corresponding        imidoester, which, by acid hydrolysis, results in the compounds        of formula In:

-   in which R, R₂ and R₃ are as defined for the compounds of formula Ik    and R₁ represents a —CO₂Alk radical,-   it being possible for the compounds of formula In themselves to be    subjected to a saponification reaction in order to obtain the    compounds of formula Io:

-   in which R, R₂ and R₃ are as defined for the compounds of formula Ik    and R₁ represents a —CO₂H radical,-   c) or to a Suzuki reaction according to the conditions described in    Synth. Commun., (1981), Vol. 11, p. 513, with phenylboronic or    heteroarylboronic derivatives in order to obtain the compounds of    formula Is:

-   in which R, R₂ and R₃ are as defined for the compound of formula Ii    and R₁ represents a substituted phenyl radical or an optionally    substituted 5- or 6-membered heteroaryl;-   OR-   D) the compounds of formula Ij in which R₁ represents an amino    radical are subjected to an acylation or sulfonylation reaction in    order to obtain the compounds of formula Ip:

-   in which R, R₂ and R₃ are as defined for the compounds of formula Ij    and R₁ represents an —NHCOAlk, —NHCO₂Alk, —NHSO₂Alk, —NHCOPh or    —NHCOCF₃ radical in which Alk and Ph are as defined for the compound    of formula I,-   it being possible for the compounds of formula Ip in which R₁    represents an —NHCOCF₃ radical to be themselves subjected to an    alkylation and then deprotection reaction, optionally followed by    another alkylation reaction, in order to obtain the compounds of    formula Iq:

-   in which R, R₂ and R₃ are as defined for the compounds of formula Ij    and R₄ and R₅ are as defined for the compound of formula I;-   OR-   E) the compounds of formula Ir in which R represents a —CO₂R₆    radical and R₆ represents an Alk radical, as obtained above in    part A) (namely by acylation of the compounds of formula (II) where    R=—COOAlk with the compounds of formula (III)), are subjected to an    acid or basic hydrolysis reaction in order to obtain the compounds    of formula It:

-   in which R₁, R₂ and R₃ are as defined for the compounds of formula    Ir and R represents a —COOH radical,-   the compounds of formula It can subsequently be subjected:-   a) either to a coupling reaction after activation of the carboxyl    functional group with, for example, the reactant BOP    [benzotriazol-1-yloxytris(dimethylamino)phosphonium    hexafluorophosphate] in the presence of a base, such as    triethylamine, according to the procedure described in Tetrahedron    Letters, (1975), 14, 1219-1222, and then addition of an amine of    formula HNR₄R₅ or of an amine of formula H₂N—CH(R₇)—(CH₂)_(m)—COOR₆    where R₆ represents an Alk radical in order to obtain the compounds    of formula Iu:

-   in which R₁, R₂ and R₃ are as defined for the compounds of formula    It,-   and, when R is a —CONH—CH(R₇)—(CH₂)_(n)—COOR₆ radical where R₆    represents an Alk radical as defined for the compounds of formula I,    these compounds can be saponified in order to obtain the compounds    of formula Iu where R is a —CONH—CH(R₇)—(CH₂)_(m)—COOR₆ radical    where R₆ represents a hydrogen atom and R₁, R₂ and R₃ are as defined    above,-   b) or to Curtius rearrangements according to the procedure described    in Synthesis, (1990), 295-299, by the action of diphenylphosphoryl    azide in the presence of triethylamine at reflux in an inert    solvent, such as toluene, and then addition of an alcohol of formula    Alk-OH in order to obtain the compounds of formula Iv:

-   in which R₁, R₂ and R₃ are as defined for the compounds of formula    It and R represents an —NHCO₂Alk radical,-   the compounds of formula Iv in which R represents an —NH—CO₂-Alk    radical where Alk represents a -tBu radical can subsequently result    in the compounds of formula Iw in which R₁, R₂, R₃, R₄ and R₅ are as    defined for the compound of formula I:

-   -   by deprotection in an acid medium, the compounds of formula Iw        where R represents an —NH₂ radical are obtained,    -   by alkylation followed by deprotection and by an optional second        alkylation, the compounds of formula Iw where R represents an        —NR₄R₅ radical can be obtained,

-   the compounds of formula Iw where R represents an —NH₂ radical can    subsequently be either acylated or sulfonylated in order to obtain    the compounds of formula Ix:

-   in which R₁, R₂ and R₃ are as defined for the compounds of formula    Iw and R represents an —NHCOAlk or —NHSO₂Alk radical;-   OR-   F) the compounds of formula Iy:

-   in which R represents an —O-benzyl radical and R₁, R₂ and R₃ are as    defined in the compounds of formula I, are subjected to a    debenzylation reaction, for example by reaction of hydrazine    hydrate, in a protic solvent, such as methanol, in the presence of    palladium-on-charcoal in order to obtain the compounds of formula    Iz:

-   in which R₁, R₂ and R₃ are as defined for the compounds of formula    Iy and R represents a hydroxyl radical, and, when R₂ or R₃    represents a nitro functional group, the compounds of formula Id in    which R₂ or R₃ represents an NH₂ radical and R₁ is as defined in the    compounds of formula I are obtained,-   the compounds of formula Iz can subsequently be subjected to a    selective O-alkylation reaction by the action at ambient temperature    of an alkyl halide in a polar solvent, such as dimethylformamide, in    the presence of an alkaline carbonate in order to obtain the    compounds of formula Iz′:

-   in which R₁, R₂ and R₃ are as defined for the compounds of formula    Iz,-   and, when R is an —O-Alk-COOR₆ radical where R₆ represents an Alk    radical as defined for the compounds of formula I, these compounds    can be saponified in order to obtain the compounds of formula Iz′    where R is an —O-Alk-COOR₆ radical where R₆ represents a hydrogen    atom and R₁, R₂ and R₃ are as defined above.

A person skilled in the art will know how to use the various reactionsas described above and illustrated in the following Schemes 1 to 6 inorder to obtain the compound of formula I while taking into account thevarious radicals situated on the molecule and capable of reacting.

In Schemes 1 to 6, the starting compounds and the reactants, when theirmethod of preparation is not described, are available commercially orare described in the literature or else can be prepared according tomethods which are described therein or which are known to a personskilled in the art.

The various alternatives A, B, C, D, E or F described above arerespectively represented by the following Schemes 1, 2, 3, 4, 5 and 6.

The compounds of formula II, in particular when R₁═H, are obtained bymethods known in the literature from suitably substituted2-aminomethylpyridines according to the following reaction schemedescribed in J. Chem. Soc., (1955), 2834-2836:

Mention may also be made of three patent applications describing thesynthesis of imidazo[1,5-a]pyridines: WO 03/070732, WO 04/064836 and WO04/046133.

The compounds of formula III in which R₂ and R₃, which are identical ordifferent, have the same definitions as for the compounds of formula Iaor Ib and X represents a chlorine atom are obtained by the action ofthionyl chloride on the corresponding benzoic acids, which arecommercially available or described in the literature.

The compounds of formula III′ in which R₂′ and R₃′ together form, withthe carbon atoms of the phenyl ring to which they are attached, a6-membered carbon ring comprising a nitrogen atom and anotherheteroatom, such as oxygen, and X represents a chlorine atom can beobtained by the action of thionyl chloride on the corresponding acidsdescribed in the literature. Mention may be made, for example, of4-oxo-2-phenyl-4H-3,1-benzoxazine-6-carboxylic acid, prepared accordingto the method described in French patent FR 2 333 511, which, bytreatment with thionyl chloride, results in the corresponding acidchloride, which is used to acylate the compounds of formula II and togive the compounds of formula Ic.

The compounds of the formula I according to the present invention arepowerful FGF-1 and -2 antagonists. Their abilities to both inhibit theformation of new vessels from differentiated endothelial cells and toblock the differentiation of CD34+ CD133+ adult human bone marrow cellsto give endothelial cells have been demonstrated in vitro. Furthermore,their ability to inhibit pathological angiogenesis has been demonstratedin vivo. Moreover, it has been demonstrated that the compounds offormula I are powerful antagonists of the FGF-1 receptor.

Generally, FGF receptors are significantly involved, via autocrine,paracrine or juxtacrine secretions, in the phenomena of deregulation ofthe stimulation of the growth of cancer cells. Moreover, FGF receptorsaffect tumor angiogenesis, which plays a predominant role both withregard to the growth of the tumor and also with regard to metastasizingphenomena.

Angiogenesis is a process for the generation of new capillary vesselsfrom preexisting vessels or by mobilization and differentiation of bonemarrow cells. Thus, both uncontrolled proliferation of endothelial cellsand mobilization of angioblasts from the bone marrow are observed inneovascularization processes of tumors. It has been shown in vitro andin vivo that several growth factors stimulate endothelial proliferationand in particular the FGF-1 or a-FGF receptor and the FGF-2 or b-FGFreceptor. These two factors induce the proliferation, the migration andthe production of proteases by endothelial cells in culture andneovascularization in vivo. The a-FGF and b-FGF receptors interact withthe endothelial cells via two categories of receptors, high affinityreceptors with a tyrosine kinase activity (FGFs) and low affinityreceptors of heparan sulfate proteoglycan type (HSPGs) situated at thesurface of the cells and in the extracellular matrices. While theparacrine role of these two factors with regard to endothelial cells iswidely described, a-FGF and b-FGF might also be involved with regard tothe cells through an autocrine process. Thus, a-FGF and b-FGF and theirreceptors represent highly relevant targets for therapies aimed atinhibiting angiogenesis processes (Keshet E. and Ben-Sasson S. A., J.Clin. Invest., (1999), Vol. 501, pp. 104-1497; Presta M., Rusnati M.,Dell'Era P., Tanghetti E., Urbinati C., Giuliani R. et al., New York:Plenum Publishers, (2000), pp. 7-34; Billottet C., Janji B., Thiery J.P. and Jouanneau J., Oncogene, (2002), Vol. 21, pp. 8128-8139).

Furthermore, systematic studies targeted at determining the expressiondue to a-FGF and b-FGF and their receptors (FGFs) with regard to varioustypes of tumor cells demonstrate that a cell response to these twofactors is functional in a great majority of human tumor lines studied.These results support the hypothesis that an antagonist of a-FGF andb-FGF might also inhibit the proliferation of tumor cells (Chandler L.A., Sosnowski B. A., Greenlees L., Aukerman S. L., Baird A. and PierceG. F., Int. J. Cancer, (1999), Vol. 58, pp. 81-451).

a-FGF and b-FGF play an important role in the growth and maintenance ofthe cells of the prostate. It has been shown, both in animal models andin man, that a detrimental change in the cellular response to thesefactors plays an essential role in the progression of prostate cancer.This is because, in these pathologies, both an increase in theproduction of a-FGF and b-FGF by the fibroblasts and the endothelialcells present in the tumor and an increase in the expression of FGFreceptors on the tumor cells are recorded. Thus, a paracrine stimulationof the cancer cells of the prostate takes place and this process wouldbe a major component of this pathology. A compound possessing anantagonist activity for FGF receptors, such as the compounds of thepresent invention, may represent a therapy of choice in thesepathologies (Giri D. and Ropiquet F., Clin. Cancer Res., (1999), Vol.71, pp. 5-1063; Doll J. A., Reiher F. K., Crawford S. E., Pins M. R.,Campbell S. C. and Bouck N. P., Prostate, (2001), Vol. 305, pp. 49-293).

Several studies show the presence of a-FGF and b-FGF and their FGFRreceptors both in human breast tumor lines (in particular MCF7) and inbiopsies of tumors. These factors would be responsible, in thispathology, for the appearance of a very aggressive phenotype whichinduces strong metastasizing. Thus, a compound possessing an antagonistactivity for FGFR receptors, such as the compounds of the formula I, mayrepresent a therapy of choice in these pathologies (Vercoutter-EdouartA-S., Czeszak X., Crépin M., Lemoine J., Boilly B., Le Bourhis X. etal., Exp. Cell. Res., (2001), Vol. 262, pp. 59-68).

Cancerous melanomas are tumors which very frequently induce metastasesand which are highly resistant to the various chemotherapy treatments.Angiogenesis processes play a predominant role in the progression of acancerous melanoma. Moreover, it has been shown that the probability ofappearance of metastases increases very strongly with the increase inthe vascularization of the primary tumor. The cells of melanomas produceand secrete various angiogenic factors, including a-FGF and b-FGF.Furthermore, it has been shown that inhibition of the cell effect ofthese two factors by the soluble FGF-1 receptor blocks in vitro theproliferation and the survival of the melanoma tumor cells and blocks invivo the tumor progression. Thus, a compound possessing an antagonistactivity for FGF receptors, such as the compounds of the presentinvention, may represent a therapy of choice in these pathologies(Rofstad E. K. and Halsor E. F., Cancer Res., (2000); Yayon A., Ma Y-S.,Safran M., Klagsbrun M. and Halaban R., Oncogene, (1997), Vol. 14, pp.2999-3009).

Glioma cells produce a-FGF and b-FGF in vitro and in vivo and possess,at their surface, various FGF receptors. This thus suggests that thesetwo factors, by autocrine and paracrine effect, play a pivotal role inthe progression of this type of tumor. Moreover, like the majority ofsolid tumors, the progression of gliomas and their ability to inducemetastases is highly dependent on the angiogenic processes in theprimary tumor. It has also been shown that FGF-1 receptor antisensesblock human astrocytoma proliferation. Furthermore, naphthalenesulfonatederivatives are described for inhibiting the cellular effects of a-FGFand b-FGF in vitro and the angiogenesis induced by these growth factorsin vivo. Intracerebral injection of these compounds induces a verysignificant increase in apoptosis and a significant decrease inangiogenesis, which is reflected by a considerable regression in gliomasin the rat. Thus, a compound possessing an antagonist activity for a-FGFand/or b-FGF and/or FGF receptors, such as the compounds of the presentinvention, may represent a therapy of choice in these pathologies(Yamada S. M., Yamaguchi F., Brown R., Berger M. S. and Morrison R. S.,Glia, (1999), Vol. 76, pp. 28-66; Auguste P., Gürsel D. B., Lemière S.,Reimers D., Cuevas P., Carceller F. et al., Cancer Res., (2001), Vol.26, pp. 61-1717).

More recently, the potential role of proangiogenic agents in leukemiasand lymphomas has been documented. This is because, generally, it hasbeen reported that cell clones in these pathologies can be eitherdestroyed naturally by the immune system or suddenly change into anangiogenic phenotype which favors their survival and then theirproliferation. This change in phenotype is induced by an overexpressionof angiogenic factors, in particular by the macrophages, and/or amobilization of these factors from the extracellular matrix (Thomas D.A., Giles F. J., Cortes J., Albitar M. and Kantarjian H. M., ActaHaematol., (2001), Vol. 207, pp. 106-190). Among angiogenic factors,b-FGF has been detected in numerous lymphoblastic and hematopoietictumor cell lines. FGF receptors are also present on the majority ofthese lines, suggesting a possible autocrine cellular effect of thea-FGF and b-FGF which induces the proliferation of these cells.Furthermore, it has been reported that the angiogenesis of the bonemarrow by paracrine effects was correlated with the progression of someof these pathologies.

More particularly, it has been shown, in CLL (chronic lymphocyticleukemia) cells, that b-FGF induces an increase in the expression ofantiapoptotic protein (Bc12), resulting in an increase in the survivalof these cells, and thus significantly participates in theircancerization. Moreover, the levels of b-FGF which are measured in thesecells are very well correlated with the stage of clinical progression ofthe disease and the resistance to the chemotherapy applied in thispathology (fludarabine). Thus, a compound possessing an antagonistactivity for FGF receptors, such as the compounds of the presentinvention, may represent a therapy of choice, either alone or incombination with fludarabine or other products active in this pathology(Thomas D. A., Giles F. J., Cortes J., Albitar M. and Kantarjian H. M.,Acta Haematol., (2001), Vol. 207, pp. 106-190); Gabrilove J. L.,Oncologist, (2001), Vol. 6, pp. 4-7).

There exists a correlation between the angiogenesis process of the bonemarrow and extramedullar diseases in CMLs (chronic myelomonocyticleukemias). Various studies demonstrate that the inhibition ofangiogenesis, in particular by a compound possessing an antagonistactivity for FGF receptors, might represent a therapy of choice in thispathology.

The proliferation and the migration of vascular smooth muscle cellscontribute to intimal hypertrophy of the arteries and thus plays apredominant role in atherosclerosis and in post-angioplasty restenosisand endarterectomy.

In vivo studies show, after lesion of the carotid by balloon injury,local production of a-FGF and b-FGF. In this same model, an anti-FGF2neutralizing antibody inhibits the proliferation of the vascular smoothmuscle cells and thus reduces intimal hypertrophy.

An FGF2 chimeric protein bound to a molecule such as saporin inhibitsthe proliferation of the vascular smooth muscle cells in vitro andintimal hypertrophy in vivo (Epstein C. E., Siegall C. B., Biro S., FuY. M. and FitzGerald D., Circulation, (1991), Vol. 87, pp. 84-778;Waltenberger J., Circulation, (1997), pp. 96-4083).

Thus, antagonists for FGF receptors, such as the compounds of thepresent invention, represent a therapy of choice, either alone or incombination with antagonist compounds for other growth factors involvedin these pathologies, such as PDGF, in the treatment of pathologiesrelated to the proliferation of the vascular smooth muscle cells, suchas atherosclerosis or post-angioplasty restenosis, or subsequent to thefitting of endovascular prostheses (stents) or during aortocoronarybypasses.

Cardiac hypertrophy occurs in response to a stress on the ventricularwall induced by overloading in terms of pressure or volume. Thisoverloading can be the consequence of numerous physiopathologicalconditions, such as hypertension, AC (aortic coarctation), myocardialinfarction and various vascular disorders. The consequences of thispathology are morphological, molecular and functional changes, such ashypertrophy of the cardiac myocytes, accumulation of matrix proteins andthe re-expression of fetal genes. b-FGF is involved in this pathology.This is because the addition of b-FGF to cultures of neonatal ratcardiomyocytes modifies the profile of the genes corresponding to thecontractile proteins, resulting in a profile of genes of fetal type.Additionally, adult rat myocytes show a hypertrophic response under theeffect of b-FGF, this response being blocked by anti-b-FGF neutralizingantibodies.

Experiments carried out in vivo on b-FGF knockout transgenic mice showthat b-FGF is the major stimulating factor of the hypertrophy of thecardiac myocytes in this pathology (Schultz Je J, Witt S. A., Nieman M.L., Reiser P. J., Engle S. J., Zhou M. et al., J. Clin. Invest., (1999),Vol. 19, pp. 104-709).

Thus, a compound, such as the compounds of the present invention,possessing an antagonist activity for the FGF receptors represents atherapy of choice in the treatment of cardiac insufficiency and anyother pathologies associated with degeneration of the cardiac tissue.This treatment can be carried out alone or in combination with currenttreatments (beta-blockers, diuretics, angiotensin antagonists,antiarrhythmics, calcium antagonists, antithrombotics, and the like).

The vascular disorders due to diabetes are characterized by adetrimental change in the vascular reactivity and in the blood flow,hyperpermeability, an exacerbated proliferative response and an increasein deposits of matrix proteins. More specifically, a-FGF and b-FGF arepresent in the preretinal membranes of patients having diabeticretinopathy, in the membranes of the underlying capillaries and in thevitreous humor of patients suffering from proliferative retinopathy. Asoluble FGF receptor capable of binding to both a-FGF and b-FGF isdeveloped in vascular disorders related to diabetes (Tilton R. G., DixonR. A. F. and Brock T. A., Exp. Opin. Invest. Drugs, (1997), Vol. 84, pp.6-1671). Thus, a compound, such as the compounds of formula I,possessing an antagonist activity for FGF receptors represents a therapyof choice, either alone or in association with compounds which areantagonists for other growth factors involved in these pathologies, suchas VEGF.

Rheumatoid arthritis (RA) is a chronic disease with an unknown etiology.While it affects numerous organs, the severest form of RA is aprogressive synovial inflammation of the joints resulting in theirdestruction. Angiogenesis appears to significantly affect theprogression of this pathology. Thus, a-FGF and b-FGF have been detectedin the synovial tissue and in the joint fluid of patients affected byRA, indicating that this growth factor is involved in the initiationand/or the progression of this pathology. In adjuvant-induced models ofarthritis (AIA) in the rat, it has been shown that the overexpression ofb-FGF increases the seriousness of the disease, whereas an anti-b-FGFneutralizing antibody blocks the progression of RA (Yamashita A.,Yonemitsu Y., Okano S., Nakagawa K., Nakashima Y., Irisa T. et al., J.Immunol., (2002), Vol. 57, pp. 168-450; Manabe N., Oda H., Nakamura K.,Kuga Y., Uchida S, and Kawaguchi H., Rheumatol., (1999), Vol. 20, pp.38-714). Thus, the compounds according to the invention represent atherapy of choice in this pathology.

It has also been described that the levels of growth factors having aproangiogenic activity, such as FGF1 and 2, were greatly increased inthe synovial fluid of patients affected by osteoarthritis. In this typeof pathology, a significant modification in the balance between the pro-and antiangiogenic factors is recorded, resulting in the formation ofnew vessels and consequently the vascularization of nonvascularizedstructures, such as articular cartilages or intervertebral disks. Thus,angiogenesis represents a key factor in bone formation (osteophytes),thus contributing to the progression of the disease. Additionally, theinnervation of the new vessels may also contribute to the chronic painassociated with this pathology (Walsh D. A., Curr. Opin., Rheumatol.,2004 Sep. 16(5), 609-15). Thus, the compounds according to the inventionrepresent a therapy of choice in this pathology.

IBD (inflammatory bowel disease) comprises two forms of chronicinflammatory diseases of the intestine: UC (ulcerative colitis) andCrohn's disease (CD). IBD is characterized by an immune dysfunctionwhich is reflected by inappropriate production of inflammatorycytokines, resulting in the establishment of a local microvascularsystem. The consequence of this angiogenesis of inflammatory origin isan intestinal ischemia induced by vasoconstriction. High circulating andlocal levels of b-FGF have been measured in patients affected by thesepathologies (Kanazawa S., Tsunoda T., Onuma E., Majima T., Kagiyama M.and Kkuchi K., American Journal of Gastroenterology, (2001), Vol. 28,pp. 96-822; Thorn M., Raab Y., Larsson A., Gerdin B. and Hallgren R.,Scandinavian Journal of Gastroenterology, (2000), Vol. 12, pp. 35-408).The compounds of the invention exhibiting a high antiangiogenic activityin a model of inflammatory angiogenesis represent a therapy of choice inthese pathologies.

FGF-1, -2 and -3 receptors are involved in chronogenesis andosteogenesis processes. Mutations resulting in the expression of alwaysactivated FGFRs have been related to a large number of human geneticdiseases reflected by malformations of the skeleton, such as Pfeiffer,Crouzon's, Apert's, Jackson-Weiss and Beare-Stevenson cutis gyratasyndromes. Some of these mutations which affect more particularly theFGF-3 receptor result in particular in achondroplasia (ACH),hypochondroplasia (HCH) and TD (thanatophoric dysplasia); ACH being thecommonest form of dwarfism. From a biochemical viewpoint, the sustainedactivation of these receptors takes place by dimerization of thereceptor in the absence of ligand (Chen L., Adar R., Yang X., MonsonegoE. O., Li C., Hauschka P. V., Yagon A. and Deng C. X., (1999), TheJourn. of Clin. Invest., Vol. 104, No. 11, pp. 1517-1525). Thus, thecompounds of the invention which exhibit an antagonist activity for thebinding of b-FGF to the FGF receptor and which thus inhibit thedimerization of the receptor represent a therapy of choice in thesepathologies.

Furthermore, it is known that the adipose tissue is one of the raretissues which, in the adult, can grow or regress. This tissue is highlyvascularized and a very dense network of microvessels surrounds eachadipocyte. These observations have resulted in the testing of the effectof antiangiogenic agents on the development of the adipose tissue in theadult. Thus, it appears that, in pharmacological models in the ob/obmouse, the inhibition of angiogenesis is reflected by a significant lossin weight of the mice (Rupnick M. A. et al., (2002), PNAS, Vol. 99, No.16, pp. 10730-10735). Thus, a compound which is an antagonist for theFGF receptors possessing a powerful antiangiogenic activity mayrepresent a therapy of choice in pathologies related to obesity.

By virtue of their toxicity and their pharmacological and biologicalproperties, the compounds of the present invention have application inthe treatment of any carcinoma which has a high degree ofvascularization (lung, breast, prostate, esophagus) or which inducesmetastases (colon, stomach, melanoma) or which is sensitive to a-FGF orto b-FGF in autocrine fashion or, finally, in pathologies of lymphomaand leukemia type. These compounds represent a therapy of choice, eitheralone or in combination with an appropriate chemotherapy. The compoundsaccording to the invention also have application in the treatment ofcardiovascular diseases, such as atherosclerosis or post-angioplastyrestenosis, in the treatment of diseases related to the complicationswhich appear subsequent to the fitting of endovascular prostheses and/oraortocoronary bypasses or other vascular grafts, and cardiachypertrophy, or vascular complications of diabetes, such as diabeticretinopathy. The compounds according to the invention also haveapplication in the treatment of chronic inflammatory diseases, such asrheumatoid arthritis or IBD. Finally, the compounds according to theinvention can be used in the treatment of achondroplasia (ACH),hypochondroplasia (HCH) and TD (thanatophoric dysplasia), and also inthe treatment of obesity.

The products according to the invention also have application in thetreatment of macular degeneration, in particular age-related maculardegeneration (or AMD). A major feature of the loss of vision in theadult is neovascularization and the resulting hemorrhages, which causemajor functional disorders in the eye and which are reflected by earlyblindness. Recently, the study of the mechanisms involved in thephenomena of ocular neovascularization has made it possible todemonstrate the involvement of proangiogenic factors in thesepathologies. By employing a laser-induced choroidal neoangiogenesismodel, it has been possible to confirm that the products according tothe invention also make it possible to modulate the neovascularizationof the choroid.

Furthermore, the products of the invention can be used in the treatmentor prevention of thrombopenia due in particular to anticancerchemotherapy. This is because it has been shown that the products of theinvention can improve the levels of circulating platelets duringchemotherapy.

Thus, according to another of its aspects, a subject matter of theinvention is medicaments which comprise a compound of formula I or anaddition salt of the latter with a pharmaceutically acceptable acid orbase or also a hydrate or a solvate of the compound of formula I.

According to another of its aspects, the present invention relates topharmaceutical compositions comprising, as active principle, a compoundof formula I according to the invention. These pharmaceuticalcompositions comprise an effective dose of at least one compoundaccording to the invention, or a pharmaceutically acceptable salt, ahydrate or a solvate of said compound, and at least one pharmaceuticallyacceptable excipient.

Said excipients are chosen according to the pharmaceutical form and themethod of administration desired (for example, the oral, sublingual,subcutaneous, intramuscular, intravenous, transdermal, transmucosal,local or rectal routes) from the usual excipients which are known to aperson skilled in the art.

The pharmaceutical compositions according to the present invention arepreferably administered orally.

In the pharmaceutical compositions of the present invention for oraladministration, the active principles can be administered in the unitadministration form as a mixture with conventional pharmaceuticalcarriers. The appropriate unit administration forms comprise, forexample, tablets, which are optionally scored, gelatin capsules,powders, granules and solutions or suspensions to be taken orally.

By way of example, a unit administration form of a compound according tothe invention in the tablet form can comprise the following components:

Compound according to the invention 50.0 mg Mannitol 223.75 mg Sodiumcroscarmellose 6.0 mg Corn starch 15.0 mg Hydroxypropylmethylcellulose2.25 mg Magnesium stearate 3.0 mg

The present invention also relates to a pharmaceutical composition asdefined above as medicament.

Another subject matter of the present invention is the use of a compoundof formula I as defined above in the preparation of a medicament of usein the treatment of diseases requiring modulation of FGFs.

Another subject matter of the present invention is the use of a compoundof formula I as defined above in the preparation of a medicament of usein the treatment of cancers, in particular carcinomas having a highdegree of vascularization, such as lung, breast, prostate and esophagealcarcinomas, cancers which induce metastases, such as colon cancer andstomach cancer, melanomas, gliomas, lymphomas and leukemias.

A compound of formula I according to the present invention can beadministered alone or in combination with one or more compound(s)possessing an antiangiogenic activity or with one or more cytotoxiccompound(s) (chemotherapy) or also in combination with treatment withradiation. Thus, another subject matter of the present invention is theuse of a compound of formula I as defined above in combination with oneor more anticancer active principle(s) and/or with radiotherapy.

Another subject matter of the present invention is the use of a compoundof formula I as defined above in the preparation of a medicament of usein the treatment of cardiovascular diseases, such as atherosclerosis orpost-angioplasty restenosis, diseases related to the complications whichappear subsequent to the fitting of endovascular prostheses and/oraortocoronary bypasses or other vascular grafts of cardiac hypertrophy,or vascular complications of diabetes, such as diabetic retinopathy.

Another subject matter of the present invention is the use of a compoundof formula I as defined above in the preparation of a medicament of usein the treatment of chronic inflammatory diseases, such as rheumatoidarthritis or IBD.

Another subject matter of the present invention is the use of a compoundof formula I as defined above in the preparation of a medicament of usein the treatment of osteoarthritis, achondroplasia (ACH),hypochondroplasia (HCH) and TD (thanatophoric dysplasia).

Another subject matter of the present invention is the use of a compoundof formula I as defined above in the preparation of a medicament of usein the treatment of obesity.

Another subject matter of the present invention is the use of a compoundof formula I as defined above in the preparation of a medicament of usein the treatment of macular degeneration, such as age-related maculardegeneration (AMD).

The compositions according to the invention for oral administrationcomprise recommended doses from 0.01 to 700 mg. There may be specificcases where higher or lower dosages are appropriate; such dosages do notdepart from the scope of the invention. According to the usual practice,the dosage appropriate to each patient is determined by the physicianaccording to the method of administration, the age, the weight and theresponse of the patient, and the degree of progression of the disease.

The present invention, according to another of its aspects, also relatesto a method for the treatment of the pathologies indicated above whichcomprises the administration, to a patient, of an effective dose of acompound according to the invention or one of its pharmaceuticallyacceptable salts or hydrates or solvates.

The following examples describe the preparation of some compounds inaccordance with the invention. These examples are not limiting and serveonly to illustrate the present invention.

The materials and intermediates, when their preparation is notexplained, are known in literature or are commercially available. Someintermediates of use in the preparation of the compounds of formula Ican also be used as final products of formula I, as will become apparentin the examples given below. Similarly, some compounds of formula I ofthe invention can be used as intermediates of use in the preparation ofother compounds of formula I according to the invention.

In that which follows:

-   -   BOC: tert-butyloxycarbonyl.    -   BOP: benzotriazol-1-yloxytris(dimethylamino)phosphonium        hexafluorophosphate.    -   DMSO: dimethyl sulfoxide.    -   The NMR spectra were measured on Bruker Avance 250 MHz, 300 MHz        and 400 MHz devices.    -   The melting points were measured on a Büchi type B-540 device.    -   M.S.: mass spectrometry, measured on an Agilent MSD1 device.

PREPARATIONS OF SYNTHETIC INTERMEDIATES Preparation I Synthesis oftert-butyl imidazo[1,5-a]pyridine-6-carboxylate

3.37 ml (14.06 mmol) of N,N-dimethylformamide di(tertbutyl)acetal areadded to 570 mg (3.52 mmol) of imidazo[1,5-a]pyridine-6-carboxylic acid[described in Bioorg. Med. Chem. Lett., (2002), 12(3), 465-470] in amixture of 5 ml of dimethylformamide and 5 ml of toluene and the mixtureis heated at 90° C. for 6 hours. 3.37 ml (14.06 mmol) ofN,N-dimethylformamide di(tert-butyl)acetal are again added to thereaction medium and the mixture is heated at 90° C. for a further 4hours. The reaction medium is poured onto water and extracted with ethylacetate. The organic phase is separated by settling, washed with asaturated aqueous sodium chloride solution, dried over sodium sulfateand concentrated under reduced pressure. The product is purified byfiltration through a bed of silica, elution being carried out with amixture of dichloromethane and methanol (98/2). After evaporation, 580mg of a beige powder are obtained. Melting point: 77° C.; ¹H NMR(d₆-DMSO): 1.59 (9H, s), 7.71 (1H, d), 7.36 (1H, s), 7.58 (1H, d), 8.56(1H, s), 9.03 (1H, s).

Preparation II Synthesis of 7-(benzyloxy)imidazo[1,5-a]pyridine

Stage A

4-(Benzyloxy)-2-(chloromethyl)pyridine

1.76 ml (24.16 mmol) of thionyl chloride are added to 2 g (9.29 mmol) of[4-(benzyloxy)pyridin-2-yl]methanol [described in J. Org. Chem., (1996),61(8), 2624] in 46 ml of dichloromethane. The reaction medium is stirredat ambient temperature for 18 hours and then concentrated under reducedpressure. The residue obtained is taken up in a saturated aqueous sodiumcarbonate solution and then extracted with dichloromethane. The organicphase is dried over sodium sulfate and then concentrated under reducedpressure. 2.1 g of a brown oil are collected. Mass spectrometry (ES+Mode): MH+=234

Stage B

1-[4-(Benzyloxy)pyridin-2-yl]methanamine

1.5 g (10.78 mmol) of hexamethylenetetramine and then 1.3 g of sodiumiodide are added to 2.1 g (8.99 mmol) of4-(benzyloxy)-2-(chloromethyl)pyridine (described in stage A) in 60 mlof dichloromethane. The reaction medium is heated at reflux for 12 hoursand then concentrated under reduced pressure. The residue obtained istaken up in 45 ml of methanol. 7.5 ml (89.90 mmol) of a 12N hydrochloricacid solution are added. The reaction medium is heated at reflux for 16hours. After addition of ethyl ether, the precipitate obtained isfiltered off and then taken up in a saturated aqueous sodium carbonatesolution. The aqueous phase is extracted with ethyl acetate, dried oversodium sulfate and then concentrated under reduced pressure. 1.1 g of abeige oil are collected. Mass spectrometry (ES+Mode): MH+=215

Stage C

0.7 g (3.27 mmol) of 1-[4-(benzyloxy)pyridin-2-yl]methanamine (describedin stage B) in 16 ml of formic acid is heated at reflux for 5 hours. Thereaction medium is concentrated under reduced pressure. The residueobtained is taken up in 7 ml of 1,2-dichloroethane. 0.6 ml (6.54 mmol)of phosphoryl chloride dissolved in 7 ml of 1,2-dichloroethane is added.After heating at reflux for 4 hours, the reaction medium is concentratedunder reduced pressure and the residue is then taken up indichloromethane. The organic phase is washed with a saturated aqueoussodium hydrogencarbonate solution, dried over sodium sulfate andconcentrated under reduced pressure. 0.97 g of a brown oil is collected.

Mass spectrometry (ES+ Mode): MH+=225; ¹H NMR (d₆-DMSO): 5.092 (2H, s),6.44-6.47 (1H, m), 7.07 (1H, m), 7.08 (1H, s), 7.37-7.49 (5H, m), 8.17(1H, s), 8.23-8.27 (1H, m)

Preparation III Synthesis of 8-(benzyloxy)imidazo[1,5-a]pyridine

This compound is prepared according to the same procedure as inpreparation II (stage C) from 2.8 g (13.25 mmol) of1-[3-(benzyloxy)pyridin-2-yl]methanamine [described in Inorg. Chem.,(2003), 42(14), 4401] by formylation with formic acid and thencyclization by reaction with phosphoryl chloride. 1.74 g of a brown oilare obtained.

Mass spectrometry (ES+ Mode): MH+=225; ¹H NMR (d₆-DMSO): 5.26 (2H, s),6.21-6.28 (1H, m), 6.55-6.60 (1H, m), 7.28-7.52 (6H, m), 7.96-7.99 (1H,m), 8.35 (1H, s)

EXAMPLES Example 1(Imidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitrophenyl)methanone

11.5 g (0.053 mol) of 3-methoxy-4-nitrobenzoyl chloride and 7.8 ml(0.056 mol) of triethylamine are added to 3 g (0.025 mol) ofimidazo[1,5-a]pyridine [described in J. Chem. Soc., (1955), 2834-2836]dissolved in 100 ml of 1,2-dichloroethane. The mixture is stirred atambient temperature for 2 hours. The reaction medium is concentratedunder reduced pressure and the residue is then taken up indichloromethane and a saturated aqueous sodium bicarbonate solution. Theorganic phase is separated by settling, washed with a saturated aqueoussodium chloride solution, dried over sodium sulfate and concentratedunder reduced pressure. The residue is taken up in dichloromethane andpurified by filtration through a bed of silica gel. After evaporation,7.1 g of a yellow solid are collected. Melting point: 183° C.; ¹H NMR(d₆-DMSO): 4.01 (3H, s), 7.35-7.40 (1H, m), 7.47-7.54 (1H, m), 7.97 (1H,s), 8.06-8.11 (3H, m), 8.15 (1H, s), 9.77 (1H, d).

Examples 2 to 4

By carrying out the preparation according to the procedure described inexample 1, the compounds of formula Ia described in table I below aresynthesized by acylation of the suitably substitutedimidazo[1,5-a]pyridines (described in international patent applicationsWO 04/046133 and WO 03/070732) with 3-methoxy-4-nitrobenzoyl chloride.

TABLE I Melting point Ex. R R₁ R₂ R₃ (° C.) 2 8-CO₂Et H OMe NO₂ 210 37-CO₂Et H OMe NO₂ 196 4 6-CO₂Me H OMe NO₂ 218 5 8-Me H OMe NO₂ 130 67-OBn H OMe NO₂ 220 7 8-OBn H OMe NO₂ 211 8 7-Me H OMe NO₂ 176

The NMR data for examples 2 to 8 in table I are presented in table I′below:

TABLE I′ Ex. ¹H NMR (d₆-DMSO) 2 1.43 (3H, t), 3.99 (3H, s), 4.47 (2H,q), 7.46 (1H, t), 7.66-8.27 (5H, m), 9.93 (1H, d) 3 1.40 (3H, t), 4.02(3H, s), 4.40 (2H, q), 7.68 (1H, d), 8.05 (2H, s), 8.15-8.20 (2H, m),8.0 (1H, s), 9.72 (1H, d) 4 3.98 (3H, s), 4.03 (3H, s), 7.79 (1H, d),8.04 (1H, s), 8.08-8.17 (4H, m), 10.31 (1H, s) 5 4.01 (3H, s), 7.23-7.30(2H, m), 7.99 (1H, s), 8.04-8.04 (1H, m), 8.04-9.62 (2H, m), 8.14 (1H,s) 6 4.01 (3H, s), 5.28 (2H, s), 7.10-7.44 (2H, m), 7.30-7.45 (4H, m),7.60-9.70 (2H, m), 7.74 (1H, s), 8.03 (1H, m), 8.12 (1H, s) 7 4.02 (3H,s), 5.42 (2H, s), 7.03-7.59 (2H, m), 7.24-7.30 (1H, t), 7.38-7.58 (4H,m), 7.97 (1H, s), 8.06 (2H, m), 8.10 (1H, s), 9.35-9.38 (1H, m) 8 2.47(3H, s), 4.02 (3H, s), 7.21-9.68 (2H, m), 7.83-7.84 (2H, m), 8.04-8.05(2H, m), 8.14 (1H, s)

Example 9 Methyl5-[(imidazo[1,5-a]pyridin-3-yl)carbonyl]-2-nitrobenzoate

5.6 g (0.023 mol) of methyl 5-(chlorocarbonyl)-2-nitrobenzoate and 3.4ml (0.024 mol) of triethylamine are added to 1.3 g (0.011 mol) ofimidazo[1,5-a]pyridine [described in J. Chem. Soc., (1955), 2834-2836]dissolved in 100 ml of 1,2-dichloroethane. The mixture is stirred atambient temperature for 4 hours. The reaction medium is concentratedunder reduced pressure and then the residue is taken up indichloromethane and a saturated aqueous sodium bicarbonate solution. Theorganic phase is separated by settling, washed with a saturated aqueoussodium chloride solution, dried over sodium sulfate and concentratedunder reduced pressure. The product is purified by column chromatographyon silica gel, elution being carried out with dichloromethane. Afterevaporation, 3.1 g of a yellow solid are collected. Melting point: 151°C.; ¹H NMR (d₆-DMSO): 3.92 (3H, s), 7.39-7.42 (1H, m), 7.50-7.54 (1H,m), 8.00 (1H, s), 8.10 (1H, d), 8.25 (1H, d), 8.69 (1H, d), 8.76 (1H,s), 9.78 (1H, d)

Example 10 tert-Butyl3-[3-(methoxycarbonyl)-4-nitrobenzoyl]imidazo[1,5-a]pyridine-6-carboxylate

This compound is obtained according to the same process as thatdescribed in example 9 by benzoylation of tert-butylimidazo[1,5-a]pyridine-6-carboxylate with methyl5-(chlorocarbonyl)-2-nitrobenzoate in the presence of triethylamine. Ayellow solid is obtained. Melting point: 170° C.; ¹H NMR (d₆-DMSO): 1.63(9H, s), 3.89 (3H, s), 7.76 (1H, d), 8.05 (1H, s), 8.12 (1H, d), 8.26(1H, d), 8.70 (1H, d), 8.77 (1H, s), 10.25 (1H, s)

Example 113-[3-(Methoxycarbonyl)-4-nitrobenzoyl]imidazo[1,5-a]pyridine-6-carboxylicacid

2.13 ml (28.68 mmol) of trifluoroacetic acid are added to 610 mg (1.43mmol) of tert-butyl3-[3-(methoxycarbonyl)-4-nitrobenzoyl]imidazo[1,5-a]pyridine-6-carboxylatein 2 ml of dichloromethane and the mixture is stirred at ambienttemperature for 5 hours. The reaction medium is concentrated underreduced pressure and then the residue obtained is taken up in acetone.The precipitate formed is filtered off, washed with acetone and dried.450 mg of a yellow powder are obtained. Melting point: 290° C.; ¹H NMR(d₆-DMSO): 3.90 (3H, s), 7.78 (1H, d), 8.04 (1H, s), 8.12 (1H, d), 8.26(1H, d), 8.68 (1H, d), 8.75 (1H, s), 10.26 (1H, s)

Example 12 Methyl5-({6-[(tert-butoxycarbonyl)amino]imidazo[1,5-a]pyridin-3-yl}carbonyl)-2-nitrobenzoate

0.55 ml (3.96 mmol) of triethylamine and 1.07 ml of tertbutanol,followed by 0.31 ml (1.40 mmol) of diphenylphosphoryl azide, are addedto 430 mg (1.16 mmol) of3-[3-(methoxycarbonyl)-4-nitrobenzoyl]imidazo[1,5-a]pyridine-6-carboxylicacid in 20 ml of toluene. The reaction medium is heated at 110° C. for 3hours and then cooled to ambient temperature. Water and a saturatedaqueous sodium bicarbonate solution are added and then the extraction iscarried out with ethyl acetate. The organic phase is separated bysettling, washed with a saturated aqueous sodium chloride solution, thendried over sodium sulfate and concentrated under reduced pressure. Theproduct is purified by column chromatography on silica gel, elutionbeing carried out with a mixture of dichloromethane and methanol (98/2).480 mg of an orange-colored solid are obtained. Melting point: 182° C.;¹H NMR (d₆-DMSO): 1.55 (9H, s), 3.92 (3H, s), 7.45 (1H, d), 7.90 (1H,s), 7.99 (1H, d), 8.24 (1H, d), 8.67 (1H, d), 8.76 (1H, s), 9.89 (1H, s)

Example 13[6-(tert-Butoxycarbonylamino)imidazo[1,5-a]pyridin-3-yl](3-methoxy-4-nitrophenyl)methanone

This compound is obtained according to the same process as thatdescribed in example 12 above by a Curtius rearrangement starting from3-(3-methoxy-4-nitrobenzoyl)imidazo[1,5-a]pyridine-6-carboxylic acidwith diphenylphosphoryl azide in the presence of tertbutanol. A yellowsolid is obtained. Melting point: 200° C.; ¹H NMR (d₆-DMSO): 1.54 (9H,s), 4.02 (3H, s), 7.42 (1H, d), 7.87 (1H, s), 8.11-7.87 (3H, m), 8.15(1H, s), 9.87 (1H, s)

Example 14 Methyl5-({6-[(tert-butoxycarbonyl)(methyl)amino]-imidazo[1,5-a]pyridin-3-yl}carbonyl)-2-nitrobenzoate

540 mg (1.23 mmol) of methyl5-({6-[(tertbutoxycarbonyl)amino]imidazo[1,5-a]pyridin-3-yl}carbonyl)-2-nitrobenzoatein 10 ml of dimethylformamide are added to 53.9 mg (1.35 mmol) of sodiumhydride (60% dispersion in oil) in 2 ml of dimethylformamide, themixture is stirred at ambient temperature for 30 minutes, then 84 μl(1.35 mmol) of methyl iodide are added and the mixture is left stirringat ambient temperature overnight. The mixture is acidified to pH=4 withan aqueous potassium hydrogensulfate solution and extracted with ethylacetate. The organic phase is washed with a saturated aqueous sodiumchloride solution, then dried over sodium sulfate and concentrated underreduced pressure. The product is purified by filtration through a bed ofsilica, elution being carried out with dichloromethane. 475 mg of anorange-colored powder are obtained. Melting point: 55° C.; ¹H NMR(d₆-DMSO): 1.46 (9H, s), 3.33 (3H, s), 3.92 (3H, s), 7.57 (1H, d), 7.98(1H, s), 8.06 (1H, d), 8.25 (1H, d), 8.68 (1H, d), 8.76 (1H, s), 9.77(1H, s)

Example 15 Methyl5-{[6-(methylamino)imidazo[1,5-a]pyridin-3-yl]carbonyl}-2-nitrobenzoate

1.3 ml of trifluoroacetic acid are added to 460 mg (1.01 mmol) of methyl5-({6-[(tert-butoxycarbonyl)(methyl)amino]imidazo[1,5-a]pyridin-3-yl}carbonyl)-2-nitrobenzoatein 5 ml of dichloromethane and the mixture is stirred at ambienttemperature overnight. The reaction medium is concentrated under reducedpressure. The residue is taken up in water and basified with a saturatedaqueous sodium bicarbonate solution and then extracted withdichloromethane. The organic phase is washed with a saturated aqueoussodium chloride solution, then dried over sodium sulfate andconcentrated under reduced pressure. 350 mg of a red powder areobtained. Melting point: 183° C.; ¹H NMR (d₆-DMSO): 2.79 (3H, d), 3.90(3H, s), 7.11 (1H, d), 7.77 (1H, s), 7.82 (1H, d), 8.31 (1H, d), 8.66(1H, d), 8.75 (1H, s), 9.01 (1H, s)

Example 16(6-Aminoimidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitrophenyl)methanone

This compound is obtained according to the same process as thatdescribed in the preceding example 15 by deprotection of the amine ofthe compound[6-(tert-butoxycarbonylamino)imidazo[1,5-a]pyridin-3-yl](3-methoxy-4-nitrophenyl)methanonewith trifluoroacetic acid. A yellow solid is obtained which is salifiedin the hydrochloride form. Melting point: 252° C.; ¹H NMR (d₆-DMSO):4.01 (3H, s), 7.14 (1H, d), 7.79 (1H, s), 7.87 (1H, d), 7.97-8.01 (2H,m), 8.13 (1H, s), 9.41 (1H, s)

Example 17N-[3-(3-methoxy-4-nitrobenzoyl)imidazo[1,5-a]pyridin-6-yl]methanesulfonamide

0.107 ml (1.38 mmol) of mesyl chloride is added to 0.40 g (1.15 mmol) of(6-aminoimidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitrophenyl)methanonehydrochloride in 10 ml of pyridine cooled to 5° C. and the mixture isallowed to return to ambient temperature and is stirred for 18 hours.The medium is taken up in 130 ml of 1N hydrochloric acid and extractedwith ethyl acetate. The organic phase is washed with a saturated aqueoussodium chloride solution, then dried over sodium sulfate andconcentrated under reduced pressure. The residue is taken up inisopropyl ether, filtered off, washed with isopropyl ether and thendried. 411 mg of a yellow solid are obtained. Melting point: 249° C.; ¹HNMR (d₆-DMSO): 3.14 (3H, s), 4.02 (3H, s), 7.39 (1H, d), 7.94 (1H, s),8.02-8.11 (3H, m), 8.13 (1H, s), 9.88 (1H, s)

Example 18N-[3-(3-Methoxy-4-nitrobenzoyl)imidazo[1,5-a]pyridin-6-yl]acetamide

1.29 ml (9.29 mmol) of triethylamine and then 0.51 ml (7.15 mmol) ofacetyl chloride are added to 0.50 g (1.43 mmol) of(6-aminoimidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitrophenyl)methanonehydrochloride in 25 ml of 1,2-dichloroethane cooled to 5° C. and thenthe mixture is allowed to return to ambient temperature and is stirredfor 18 hours. The medium is taken up in water, basified with a sodiumbicarbonate solution and extracted with dichloromethane. The organicphase is washed with a saturated aqueous sodium chloride solution, thendried over sodium sulfate and concentrated under reduced pressure. Theproduct is purified by column chromatography on silica gel, elutionbeing carried out with a mixture of dichloromethane and acetone (90/10).316 mg of a yellow solid are obtained. Melting point: 257° C.; ¹H NMR(d₆-DMSO): 2.15 (3H, s), 4.01 (3H, s), 7.45 (1H, d), 7.92 (1H, s),8.00-8.06 (3H, m), 8.13 (1H, s), 10.62 (1H, s)

Example 19 Methyl2-(benzoylamino)-5-[(imidazo[1,5-a]pyridin-3-yl)carbonyl]benzoate

5.2 ml (0.037 mol) of triethylamine and then, under nitrogen atmosphereat 0° C., 10 g (0.035 mol) of4-oxo-2-phenyl-4H-3,1-benzoxazine-6-carbonyl chloride are added to 1.97g (0.017 mol) of imidazo[1,5-a]pyridine [described in J. Chem. Soc.,(1955), 2834-2836] in 100 ml of acetonitrile. After stirring at ambienttemperature for 22 hours, the reaction medium is filtered. The residueobtained is washed with ethyl acetate, with water and with acetone andthen dried. 0.32 g (2.65 mmol) of N,N-dimethylpyridine-4-amine is addedto 9.75 g (0.026 mol) of the yellow solid obtained above in 50 ml ofmethanol and 50 ml of N,N-dimethylformamide. After heating at reflux for22 hours, the reaction medium is filtered. The residue is washed withwater and then dried. The product is purified by column chromatographyon silica gel, elution being carried out with a mixture ofdichloromethane and methanol (99.9/0.1). 3.67 g of a yellow solid areobtained. Melting point: 218° C.; ¹H NMR (CDCl₃): 4.05 (3H, s),7.08-7.09 (1H, m), 7.27-7.29 (1H, m), 7.57-7.60 (3H, m), 7.76-7.81 (2H,m), 8.12 (2H, d), 8.78 (1H, d), 9.15 (1H, d), 9.28 (1H, s), 9.88 (1H, d)

Example 20(1-Bromoimidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitrophenyl)methanone

3.51 g (0.043 mol) of sodium acetate are added to 9.8 g (0.033 mol) of(imidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitrophenyl)methanone obtainedin example 1 in 170 ml of chloroform, followed, dropwise, by a solutionof 1.85 ml (0.036 mol) of bromine in 15 ml of chloroform, the mediumbeing maintained at ambient temperature. On completion of theintroduction, the mixture is stirred for a further 1 hour at the sametemperature. The reaction medium is poured onto a saturated aqueoussodium bicarbonate solution and extracted with dichloromethane. Theorganic phase is separated by settling, washed with an aqueous sodiumchloride solution, dried over sodium sulfate and concentrated underreduced pressure. The residue is taken up in a toluene/dichloromethanemixture and then purified by filtration through a bed of silica gel,elution being carried out with toluene. After evaporation, 7.71 g of ayellow solid are collected. Melting point: 189° C.; ¹H NMR (CDCl₃): 4.10(3H, s), 7.23-7.29 (1H, m), 7.41-7.46 (1H, m), 7.78 (1H, d), 7.96 (1H,d), 8.14-8.20 (2H, m), 9.90 (1H, d)

Examples 21 to 24

By carrying out the operation like the preparation described in example20, the compounds of formula Ii described in table II below aresynthesized by bromination of the compounds of formula I (with R₁═H) inthe presence of bromine and sodium acetate.

TABLE II Melting point Ex. R R₁ R₂ R₃ (° C.) 21 H Br CO₂Me NO₂ 172 22 HBr CO₂Me NHCO-Ph 209 23 7-CONHMe Br OMe NO₂ 281 24 7-CO₂Et Br OMe NO₂204

The NMR data for examples 21 to 24 in table II are presented in tableII′ below:

TABLE II′ Ex. ¹H NMR 21 (d₆-DMSO): 3.92 (3H, s), 7.48-7.67 (2H, m), 7.92(1H, d), 8.27 (1H, d), 8.62 (2H, m), 9.75 (1H, d) 22 (CDCl₃): 4.08 (3H,s), 7.13-7.16 (1H, m), 7.30-7.31 (1H, m), 7.58-7.62 (3H, m), 7.76 (1H,d), 8.13 (2H, d), 8.82 (1H, d), 9.15 (1H, d), 9.28 (1H, s), 9.89 (1H, d)23 (d₆-DMSO): 2.86 (3H, d), 4.01 (3H, s), 7.76-7.96 (2H, m), 7.96-9.72(2H, m), 8.03-8.36 (1H, m), 8.36 (1H, s), 8.96 (1H, m) 24 (CDCl₃):1.43-1.71 (3H, t), 4.11 (3H, s), 4.47-4.57 (2H, q), 7.71-7.98 (2H, m),8.18-9.85 (2H, m), 8.22 (1H, s), 8.47 (1H, s)

Example 25(3-Methoxy-4-nitrophenyl)[1-(4-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl]methanone

0.447 g (0.003 mol) of 4-methoxyphenylboronic acid, 2.24 g (0.009 mol)of K₃PO₄.H₂O and then 0.131 g (0.011 mol) oftetrakis(triphenylphosphine)palladium(0) are added to 0.850 g (0.023mol) of(1-bromoimidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitrophenyl)methanoneobtained in example 20 in 30 ml of dioxane under an argon atmosphere.The mixture is heated at reflux for 1 hour. The reaction medium ispoured onto water and extracted with ethyl acetate. The organic phase isseparated by settling, washed with a saturated aqueous sodium chloridesolution, dried over sodium sulfate and concentrated under reducedpressure. The product is purified by filtration through silica gel,elution being carried out with a dichloromethane/cyclohexane (2/1)mixture and then with dichloromethane. After evaporation, 0.850 g of anorange solid is collected. Melting point: 185° C.; ¹H NMR (d₆-DMSO):3.85 (3H, s), 4.06 (3H, s), 7.12 (2H, d), 7.41-7.44 (1H, m), 7.54-7.58(1H, m), 7.95 (2H, d), 8.08-8.10 (2H, m), 8.34 (1H, d), 8.36 (1H, s),9.81 (1H, d)

Examples 26 to 58

By carrying out the operation according to the preparation described inexample 25, the compounds of formula Is described in table III below aresynthesized by coupling of Suzuki type of the brominated compounds ofgeneral formula II with phenylboronic or heteroarylboronic derivatives,the experimental conditions (catalysts, ligands, bases) being variedaccording to the compounds to be obtained.

TABLE III M.p. Catalyst/ (° C.) Ligand/ or Ex. R R₁ R₂ R₃ Base M.S. 26 H2-thienyl OMe NO₂ Pd(t-Bu₃)₂/ 206 Pd₂dba₃ Na₂CO₃ 27 H 4-pyridinyl OMeNO₂ PdCl₂dppf 230 Na₂CO₃ 28 H 3-furyl OMe NO₂ Pd(PPh₃)₄ 225 Na₂CO₃ 29* H3-pyridinyl OMe NO₂ PdCl₂dppf 238 Na₂CO₃ 30 H 2-(5-carboxy- OMe NO₂Pd(t-Bu₃)₂/ 232 thienyl) Pd₂dba₃ Na₂CO₃ 31 H phenyl OMe NO₂ Pd(PPh₃)₄167 Na₂CO₃ 32 H 4-fluorophenyl OMe NO₂ Pd(PPh₃)₄ 240 Na₂CO₃ 33 H2-methoxyphenyl OMe NO₂ Pd(PPh₃)₄ 186 Na₂CO₃ 34 H 3-methoxyphenyl OMeNO₂ Pd(PPh₃)₄ 132 Na₂CO₃ 35 H 3-carboxyphenyl OMe NO₂ Pd(PPh₃)₄ 303Na₂CO₃ 36 H 4-chlorophenyl OMe NO₂ Pd(PPh₃)₄ 233 Na₂CO₃ 37 H3-chlorophenyl OMe NO₂ Pd(PPh₃)₄ 233 Na₂CO₃ 38 H N-BOC-2- OMe NO₂Pd(PPh₃)₄ MH+ = 463 pyrrolyl Na₂CO₃ 39 H 3-thienyl OMe NO₂ Pd(PPh₃)₄ 194Na₂CO₃ 40 H 4-methoxyphenyl CO₂Me NHCOPh Pd(PPh₃)₄ 243 K₃PO₄•H₂O 41 H2-methoxyphenyl CO₂Me NO₂ Pd(PPh₃)₄ 145 K₃PO₄•H₂O 42 H 3-thienyl CO₂MeNO₂ Pd(t-Bu₃)₂/ 172 Pd₂dba₃ K₃PO₄•H₂O 43 H 3-methoxyphenyl CO₂Me NO₂Pd(PPh₃)₄ 98 K₃PO₄•H₂O 44 H 2-thienyl CO₂Me NO₂ Pd(t-Bu₃)₂/ 135 Pd₂dba₃K₃PO₄•H₂O 45* H 3-pyridinyl CO₂Me NO₂ PdCl₂dppf 195 K₃PO₄•H₂O 46 H4-methoxy- OMe NO₂ PdCl₂dppf 246 pyridin-3-yl K₃PO₄•H₂O 47 H 3-furylCO₂Me NO₂ Pd(PPh₃)₄ 151 K₃PO₄•H₂O 48 7- 3-carboxyphenyl OMe NO₂Pd(PPh₃)₄ 328 CONHMe Na₂CO₃ 49 7-CO₂Et 3-methoxyphenyl OMe NO₂ Pd(PPh₃)₄212 K₃PO₄•H₂O 50 7-CO₂Et 4-methoxy- OMe NO₂ PdCl₂dppf 208 pyridin-3-ylK₃PO₄•H₂O 51 H 4-carboxyphenyl OMe NO₂ Pd(PPh₃)₄ 356 Na₂CO₃ 52 H4-fluorophenyl CO₂Me NO₂ Pd(PPh₃)₄ 180 K₃PO₄•H₂O 53 H 4-methoxy- CO₂MeNO₂ PdCl₂dppf 192 pyridin-3-yl K₃PO₄•H₂O 54 H 3-fluoro-4- OMe NO₂Pd(PPh₃)₄ 211 methoxyphenyl Na₂CO₃ 55 H 3-fluorophenyl OMe NO₂ Pd(PPh₃)₄214 Na₂CO₃ 56 H 4-chlorophenyl CO₂Me NO₂ Pd(PPh₃)₄ MH+ = 436 K₃PO₄•H₂O57 H 3-carboxyphenyl OMe NHSO₂- Pd(PPh₃)₄ 145 Me Na₂CO₃ 58 H —Ph-3-CO₂MeOMe NO₂ Pd(PPh₃)₄ 227 K₃PO₄•H₂O *The pinacol boronate derivatives areused instead of the corresponding boronic acids. BOC =tert-butoxycarbonyl

The NMR data for examples 26 to 58 in table III are presented in tableIII′ below:

TABLE III′ EX ¹H NMR (d₆-DMSO) or M.S. 26 4.02 (3H, s), 7.24 (1H, t),7.47-7.65 (4H, m), 7.80-7.82 (1H, m), 7.82-7.99 (2H, m), 8.52 (1H, d),8.55 (1H, s), 9.76 (1H, d) 27 4.06 (3H, s), 7.45-7.71 (2H, m), 8.02 (2H,m), 8.04 (2H, m), 8.30 (1H, s), 8.55 (1H, d), 8.69 (2H, m), 9.84 (1H, d)28 MH+ = 364 29 4.12 (3H, s), 7.42-7.51 (3H, m), 7.97 (1H, d), 8.15 (1H,d), 8.29 (2H, m), 8.39 (1H, s), 8.68 (1H, d), 9.25 (1H, s), 10.00 (1H,d) 30 4.08 (3H, s), 7.47-7.69 (2H, m), 7.76-7.83 (2H, m), 8.03-8.13 (2H,m), 8.39 (1H, s), 8.47 (1H, d), 9.84 (1H, d) 31 3.92 (3H, s), 7.32-7.80(9H, m), 8.34 (1H, s), 8.40 (1H, d), 9.85 (1H, d) 32 4.03 (3H, s),7.35-7.62 (4H, m), 8.03-8.81 (4H, m), 8.30 (1H, s), 8.38 (1H, d), 9.84(1H, d) 33 3.85 (3H, s), 4.04 (3H, s), 7.11-7.51 (5H, m), 7.64 (1H, d),7.88 (1H, d), 8.05-8.30 (2H, m), 8.30 (1H, s), 9.81 (1H, d) 34 3.86 (3H,s), 4.05 (3H, s), 7.02 (1H, m), 7.42-7.60 (5H, m), 8.08 (2H, m),8.35-8.39 (2H, m), 9.84 (1H, d) 35 4.08 (3H, s), 7.34-8.69 (10H, m),9.79 (1H, m) 36 4.03 (3H, s), 7.42-7.65 (4H, m), 8.04-8.08 (4H, m), 8.31(1H, s), 8.40 (1H, d), 9.84 (1H, d) 37 4.07 (3H, s), 7.45-7.64 (4H, m),8.0-8.03 (4H, m), 8.35 (1H, s), 8.43 (1H, d), 9.84 (1H, d) 38 1.18 (9H,s), 4.02 (3H, s), 6.43 (1H, m), 6.63 (1H, m), 7.43-7.56 (3H, m), 7.89(1H, d), 8.03 (1H, d), 8.12-8.15 (2H, m), 9.83 (1H, d) 39 4.09 (3H, s),7.23-7.26 (1H, m), 7.45-7.65 (3H, m), 7.81 (1H, d), 7.99-8.11 (2H, m),8.44 (1H, m), 8.52 (1H, s), 9.84 (1H, d) 40 (CDCl₃): 3.94 (3H, s), 4.09(3H, s), 7.09-7.13 (3H, m), 7.30-7.36 (1H, m), 7.59-7.62 (3H, m), 7.98(2H, d), 8.09-8.16 (3H, m), 8.99 (1H, d), 9.16 (1H, d), 9.61 (1H, s),9.98 (1H, d) 41 3.86 (3H, s), 3.91 (3H, s), 7.12-7.63 (5H, m), 7.63 (1H,d), 7.92 (1H, d), 8.24 (1H, d), 8.74-8.80 (2H, m), 9.81 (1H, d) 42 3.93(3H, s), 7.43-7.77 (2H, m), 7.78-7.79 (2H, m), 8.18 (1H, s), 8.24 (1H,d), 8.45 (1H, d), 8.78 (1H, d), 8.90 (1H, s), 9.85 (1H, d) 43 3.95 (3H,s), 4.00 (3H, s), 7.02 (1H, d), 7.22 (1H, t), 7.45-7.56 (4, m), 8.01(1H, d), 8.18 (1H, d), 8.06 (1H, d), 9.98 (1H, d) 44 4.02 (3H, s),7.13-7.44 (3H, m), 7.63 (1H, d), 8.03 (1H, d), 8.17 (1H, d), 8.78 (1H,m), 8.90 (1H, d), 9.05 (1H, s), 9.96 (1H, d) 45 3.92 (3H, s), 7.44-7.60(3H, m), 8.25 (1H, d), 8.44 (1H, d), 8.45 (1H, d), 8.61 (1H, d), 8.81(1H, d), 8.85 (1H, s), 9.24 (1H, s), 9.83 (1H, d) 46 3.93 (3H, s), 4.04(3H, s), 7.00 (1H, d), 7.41-7.61 (2H, m), 8.05-8.13 (2H, m), 8.29-8.41(3H, m), 8.82 (1H, s), 9.84 (1H, d) 47 3.93 (3H, s), 7.11 (1H, d),7.44-7.62 (2H, m), 7.89 (1H, d), 8.25 (1H, d), 8.35 (1H, d), 8.51 (1H,s), 8.77 (1H, d), 8.89 (1H, s), 9.85 (1H, d) 48 2.85-2.89 (3H, d), 4.09(3H, s), 7.70-8.78 (2H, m), 7.73-7.78 (2H, m), 7.96-8.1 (1H, m),8.06-9.54 (2H, m), 8.32 (1H, s), 8.34 (1H, m), 8.35 (1H, s), 8.95 (1H,m), 13.2 (1H, m) 49 1.35-1.40 (3H, t), 3.86 (3H, s), 4.05 (3H, s),4.37-4.45 (2H, q), 7.04-7.54 (2H, m), 7.46-7.54 (2H, m), 7.68-9.77 (2H,m), 8.08-8.09 (2H, m), 8.35 (1H, s), 8.65 (1H, s) 50 1.37-1.43 (3H, t),3.97 (3H, s), 4.05 (3H, s), 7.15-7.75 (2H, m), 7.97 (1H, m), 8.10 (1H,m), 8.11-9.80 (2H, m), 8.30 (1H, m), 8.30-8.75 (3H, m), 8.70 (1H, m) 514.07 (3H, s), 7.40-7.63 (2H, m), 7.57-8.14 (6H, m), 8.38 (1H, m),8.40-9.88 (2H, m) 52 3.94 (3H, s), 7.36-7.45 (3H, m), 7.62-8.09 (2H, m),8.24-8.40 (2H, m), 8.75-9.84 (2H, m), 8.85 (1H, m) 53 3.92 (3H, s), 3.94(3H, s), 6.98-8.25 (2H, m), 7.39-7.61 (2H, m), 8.28-8.83 (2H, m),8.37-9.83 (2H, m), 8.80 (1H, m) 54 3.92 (3H, s), 4.05 (3H, s), 7.32-7.41(2H, m), 7.58-8.09 (2H, m), 7.82-8.09 (2H, m), 8.32 (1H, m), 8.36-9.84(2H, m) 55 4.05 (3H, s), 7.24-7.45 (2H, m), 7.57-7.62 (2H, m), 7.86 (1H,m), 7.89 (1H, m), 8.08-8.09 (2H, m), 8.30 (1H, s), 8.41-9.84 (2H, m) 563.92 (3H, s), 7.38-7.61 (2H, m), 7.57-8.06 (4H, m), 7.68-8.36 (2H, m),8.53 (1H, m), 9.83 (1H, m) 57 3.13 (3H, s), 4.00 (3H, s), 7.35-7.67 (4H,m), 7.94-8.07 (2H, m), 8.26-8.44 (2H, m), 8.44 (1H, s), 8.64 (1H, s),9.3 (1H, m), 9.81-9.84 (1H, m), 13 (1H, m) 58 (CDCl₃): 4.01 (3H, s),4.16 (3H, s), 7.20-7.66 (2H, m), 7.29-7.49 (1H, m), 7.98-8.22 (2H, m),8.01-8.18 (2H, m), 8.21-10.00 (2H, m), 8.55 (1H, s), 8.65 (1H, s)

Example 593-(3-Methoxy-4-nitrobenzoyl)imidazo[1,5-a]pyridine-6-carboxamide

0.16 ml (1.12 mmol) of triethylamine and then 0.49 g (1.12 mmol) of BOPare added to 0.346 g (1.01 mmol) of3-(3-methoxy-4-nitrobenzoyl)imidazo[1,5-a]pyridine-6-carboxylic acidobtained in example 182 in 10 ml of N,N-dimethylformamide. The reactionmedium is stirred at ambient temperature for 30 minutes, then 1.35 ml ofa 1N solution of ammonia in tetrahydrofuran are added and the mixture isstirred at ambient temperature for 18 hours. The precipitate formed isfiltered off and then washed with water. 0.25 g of a yellow solid iscollected. Melting point: 289° C.; ¹H NMR (d₆-DMSO): 4.02 (3H, s), 7.82(1H, d), 7.98 (1H, s), 8.06-8.10 (3H, m), 8.15 (1H, s), 10.21 (1H, s)

Examples 60 to 69

By carrying out the operation according to the preparation described inexample 59, the compounds of general formula Iu described in table IVbelow are synthesized by peptide coupling of the3-(3-methoxy-4-nitrobenzoyl)imidazo[1,5-a]pyridine-6-carboxylic acidobtained in example 182 or the3-(3-methoxy-4-nitrobenzoyl)imidazo[1,5-a]pyridine-7-carboxylic acidobtained in example 184 with amines or amino acid esters in the presenceof BOP as coupling reagent.

TABLE IV Melting point Ex. R R₁ R₂ R₃ (° C.) 60 7-CONHCH₂CO₂Et H OMe NO₂196 61 (R)-7-CONHCH(CH₃)CO₂Me H OMe NO₂ 208 62 (S)-7-CONHCH(CH₃)CO₂Me HOMe NO₂ 207 63 (S)-7-CONHCH(CH₂OH)CO₂CH₃ H OMe NO₂ 204 64 6-CONHCH₂CO₂MeH OMe NO₂ 221 65 (S)-6-CONHCH(Bn)CO₂Me H OMe NO₂ 230 666-CONHCH₂CH₂CO₂Me H OMe NO₂ 190 67 (S)-6-CONHCH(CH₂OH)CO₂CH₃ H OMe NO₂202 68 (S)-6-CONHCH(CH₃)CO₂Me H OMe NO₂ 225 69 6-CONHMe H OMe NO₂ 237

The NMR data for examples 60 to 69 in table IV are presented in tableIV′ below:

TABLE IV′ Ex. ¹H NMR (d₆-DMSO) 60 1.21-1.25 (3H, t), 4.02 (3H, s),4.07-4.09 (2H, d), 4.12-4.19 (2H, q), 7.67-7.70 (1H, m), 8.05-8.16 (4H,m), 8.56 (1H, s), 9.30-9.34 (1H, t), 9.72-9.74 (1H, m) 61 1.44-1.47 (3H,d), 3.68 (3H, s), 4.52-4.57 (2H, m), 7.69-7.72 (2H, m), 8.05-8.06 (2H,m), 8.15-8.17 (2H, m), 8.59-8.60 (1H, m), 9.16-9.18 (1H, d), 9.70-9.73(1H, m) 62 1.44-1.47 (3H, d), 3.68 (3H, s), 4.02 (3H, s), 4.50-4.59 (1H,m), 7.69-9.73 (2H, m), 8.05-8.17 (2H, m), 8.06-8.16 (2H, m), 8.59 (1H,s), 9.16-9.18 (1H, d) 63 3.68 (3H, s), 3.82-3.86 (2H, m), 4.02 (3H, s),4.57-4.63 (1H, m), 5.11-5.15 (1H, t), 7.70-9.74 (2H, m), 8.06 (2H, m),8.16 (2H, m), 9.01-9.03 (1H, d) 64 3.71 (3H, s), 4.03 (3H, s), 4.12 (2H,d), 7.82 (1H, d), 8.02-8.17 (5H, m), 10.20 (1H, s) 65 3.69 (3H, s), 4.03(3H, s), 4.74-4.79 (1H, m), 7.22-7.39 (5H, m), 7.74 (1H, d), 8.0 (1H,s), 8.07-8.17 (4H, m), 10.15 (1H, s) 66 2.67 (2H, t), 3.57 (2H, m), 3.65(3H, s), 4.03 (3H, s), 7.77 (1H, d), 8.00 (1H, s), 8.07-8.17 (4H, m),10.20 (1H, s) 67 3.69 (3H, s), 3.84-3.89 (2H, m), 4.02 (3H, s),4.60-4.65 (1H, m), 7.86 (1H, d), 8.01 (1H, s), 8.05-8.16 (4H, m), 10.25(1H, s) 68 1.47 (3H, d), 3.70 (3H, s), 4.03 (3H, s), 7.85 (1H, d), 8.01(1H, s), 8.04-8.17 (4H, m), 10.22 (1H, s) 69 2.86 (3H, d), 4.02 (3H, s),7.83 (1H, d), 7.98 (1H, s), 8.04-8.11 (2H, m), 8.15 (1H, s), 10.18 (1H,s)

Example 703-(3-Methoxy-4-nitrobenzoyl)-N,N-dimethylimidazo[1,5-a]pyridine-8-carboxamide

0.17 ml (2.36 mmol) of thionyl chloride and then 30 μl ofN,N-dimethylformamide are added to 0.318 g (0.88 mmol) of3-(3-methoxy-4-nitrobenzoyl)imidazo[1,5-a]pyridine-8-carboxylic acidobtained in example 183 in 10 ml of dichloromethane. The mixture isheated at reflux for 2 hours. The reaction medium is concentrated underreduced pressure. The residue obtained is added to 5 ml of a 2N solutionof dimethylamine in tetrahydrofuran. After stirring at ambienttemperature for 18 h, the reaction medium is concentrated under reducedpressure. The residue is taken up in dichloromethane. The organic phaseis washed with a 1N aqueous hydrochloric acid solution and then with asaturated aqueous sodium chloride solution, dried over sodium sulfateand concentrated under reduced pressure. The residue is purified bycolumn chromatography on silica gel, elution being carried out withdichloromethane and then a dichloromethane/methanol (99/1) mixture. 0.19g of a yellow solid is collected. Melting point: 176° C.; ¹H NMR(d₆-DMSO): 4.02 (3H, s), 7.39 (1H, t), 7.53 (1H, d), 7.83 (1H, s),8.0-8.12 (3H, m), 9.75 (1H, d)

Examples 71 to 74

By carrying out the operation according to the preparation described inexample 70, the compounds of general formula Iu described in table Vbelow are synthesized by coupling the acid functional group of thecompounds of formula It with the corresponding amine.

TABLE V Ex. R R₁ R₂ R₃ M.p. (° C.) 71 7-CONHMe H OMe NO₂ 255° C. 727-CONH₂ H OMe NO₂ 279° C. 73 7-CONMe₂ H OMe NO₂ 184° C. 74 8-CONHMe HOMe NO₂ 258

The NMR data for examples 71 to 74 in table V are presented in table V′below:

TABLE V′ Ex. ¹H NMR (d₆-DMSO) 71 2.35 (3H, s), 2.85 (3H, d), 4.02 (3H,s), 7.70-8.06 (2H, m), 7.74 (2H, m), 7.85 (1H, s), 8.12-9.73 (2H, m),8.55 (1H, s), 8.93 (1H, m) 72 4.99 (3H, s), 7.55-8.14 (2H, m), 8.03 (1H,s), 8.04 (1H, s), 8.14-9.70 (2H, m), 8.37 (1H, s), 8.58 (1H, s) 73 3.04(6H, m), 4.02 (3H, s), 7.34-8.16 (2H, m), 8.02 (1H, s), 8.06 (1H, s),8.15-9.73 (2H, m) 74 2.87-2.89 (3H, d), 4.02 (3H, s), 7.39-7.45 (1H, t),7.82-9.85 (2H, m), 8.05 (2H, m), 8.08 (1H, m), 8.22 (1H, m), 8.79-8.81(1H, m)

Example 753-(3-Methoxy-4-nitrobenzoyl)imidazo[1,5-a]pyridine-1-carbonitrile

2.17 g (18.48 mmol) of zinc cyanide and then 1.07 g (0.93 mmol) oftetrakis(triphenylphosphine)palladium(0) are added under a nitrogenatmosphere to 6.94 g (18.45 mmol) of(1-bromoimidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitrophenyl)methanoneobtained in example 20 in 160 ml of N,N-dimethylformamide. The reactionmedium is heated at 90° C. for 17 h. The precipitate obtained isfiltered off, washed with water, then with a saturated aqueous sodiumbicarbonate solution and with water. After drying, 5.9 g of a yellowsolid are collected. Melting point: 219° C.; ¹H NMR (d₆-DMSO): 4.01 (3H,s), 7.53-7.55 (1H, m), 7.76-7.81 (1H, m), 7.95-8.01 (2H, m), 8.08 (1H,d), 8.19 (1H, d), 9.70 (1H, d)

Example 76(1-Aminoimidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitrophenyl)methanone

8.67 g (26.61 mmol) of cesium carbonate and then 4.5 ml (26.82 mmol) ofbenzophenone imine are added, under a nitrogen atmosphere, to 5 g (13.29mmol) of(1-bromoimidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitrophenyl)methanoneobtained in example 20 in 66 ml of N,N-dimethylformamide. After stirringfor 30 minutes, 1.66 g (2.67 mmol) of2,2′-bis(diphenylphosphino)-1,1′-binaphthalene and then 1.22 g (1.33mmol) of tris(dibenzylideneacetone)dipalladium(0) are added. Thereaction medium is heated for 3 hours and then concentrated underreduced pressure. The residue is taken up in a mixture ofdichloromethane and water. The organic phase is separated by settling,dried over sodium sulfate and concentrated under reduced pressure. Theresidue is taken up in 250 ml of tetrahydrofuran and 135 ml of a 2Naqueous hydrochloric acid solution are added. After stirring at ambienttemperature for one hour, the reaction medium is concentrated underreduced pressure. The solid residue obtained is taken up in acetone,filtered off, washed with acetone and then with ethyl ether and dried.3.43 g of a brown solid are collected. Melting point: 214° C.; ¹H NMR(d₆-DMSO): 4.02 (3H, s), 7.29-7.36 (2H, m), 7.96-8.04 (2H, m), 8.11 (1H,d), 8.16 (1H, s), 9.78 (1H, d)

Example 773-Methoxy-N-[3-(3-methoxy-4-nitrobenzoyl)imidazo[1,5-a]pyridin-1-yl]benzamide

0.78 ml (5.05 mmol) of triethylamine and then 1.17 g (2.65 mmol) of BOPare added, under a nitrogen atmosphere, to 0.8 g (2.29 mmol) of3-methoxybenzoic acid in 20 ml of acetonitrile. After stirring atambient temperature for 30 minutes, 0.8 g (2.29 mmol) of(1-aminoimidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitrophenyl)methanoneobtained in example 76 is added and then the mixture is heated at 80° C.for 20 hours. The reaction medium is taken up in a mixture of water andethyl acetate. The organic phase is separated by settling, washed with asaturated aqueous sodium chloride solution, dried over sodium sulfateand concentrated under reduced pressure. The residue is purified bycolumn chromatography on silica gel, elution being carried out with adichloromethane/acetone (99/1) mixture. 0.618 g of an orange-coloredsolid is collected. Melting point: 167° C.; ¹H NMR (d₆-DMSO): 3.87 (3H,s), 4.02 (3H, s), 7.21 (1H, d), 7.41-7.49 (3H, m), 7.63-7.66 (2H, m),7.95-8.10 (3H, m), 8.11 (1H, s), 9.80 (1H, d)

Example 78N-[3-(3-Methoxy-4-nitrobenzoyl)imidazo[1,5-a]pyridin-1-yl]acetamide

0.54 ml (3.84 mmol) of triethylamine and then 0.21 ml (2.95 mmol) ofacetyl chloride are added, under a nitrogen atmosphere, to 0.8 g (2.56mmol) of(1-aminoimidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitrophenyl)methanoneobtained in example 76 in 20 ml of 1,2-dichloroethane. The reactionmedium is stirred at ambient temperature for 16 hours and then taken upin a mixture of dichloromethane and water. The organic phase isseparated by settling, dried over sodium sulfate and concentrated underreduced pressure. The residue obtained is purified by columnchromatography on silica gel, elution being carried out with adichloromethane/acetone (94/6) mixture. 0.523 g of an orange solid iscollected. Melting point: 256° C.; ¹H NMR (d₆-DMSO): 2.14 (3H, s), 4.02(3H, s), 7.34-7.44 (2H, m), 7.94-8.08 (3H, m), 8.09 (1H, s), 9.75 (1H,d)

Example 79(3-Methoxy-4-nitrophenyl)[1-(methylamino)imidazo[1,5-a]pyridin-3-yl]methanone

Stage A

2,2,2-Trifluoro-N-[3-(3-methoxy-4-nitrobenzoyl)imidazo[1,5-a]pyridin-1-yl]acetamide

This compound is prepared according to the same process as thatdescribed in example 78 by acylation of 1.2 g (3.44 mmol) of(1-aminoimidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitrophenyl)methanonehydrochloride with trifluoroacetic anhydride in 1,2-dichloroethane inthe presence of triethylamine. 1.08 g of a yellow solid are obtained.Melting point: 228° C.; ¹H NMR (d₆-DMSO): 4.03 (3H, s), 7.43-7.47 (1H,m), 7.51-7.55 (1H, m), 7.93-7.99 (2H, m), 8.04-8.11 (2H, m), 9.76 (1H,d)

Stage B

0.121 g (3.03 mmol) of sodium hydride (60% dispersion in oil) is added,at 0° C., to a solution of 1.03 g (2.52 mmol) of2,2,2-trifluoro-N-[3-(3-methoxy-4-nitrobenzoyl)imidazo[1,5-a]pyridin-1-yl]acetamidein 35 ml of dimethylformamide. The reaction medium is stirred at thistemperature for 1 hour and then 0.189 ml (3.03 mmol) of methyl iodide isadded. On completion of the introduction, the mixture is allowed toreturn to ambient temperature and is stirred for 20 hours. 20 ml ofmethanol and then 0.523 g (3.78 mmol) of potassium carbonate are addedand the mixture is stirred at ambient temperature for 2 hours. Thereaction medium is poured onto water and extracted with dichloromethane.The organic phase is separated by settling, washed with water, driedover sodium sulfate and concentrated under reduced pressure. 0.86 g of ared solid is obtained, which solid is salified in the hydrochlorideform. 625 mg of a red solid are obtained. Melting point: 208° C.; ¹H NMR(d₆-DMSO): 3.00 (3H, s), 4.04 (3H, s), 7.33-7.36 (2H, m), 7.99-8.09 (3H,m), 8.59 (1H, s), 9.89 (1H, d)

Example 80 N-[3-(3-Methoxy-4-nitrobenzoyl)imidazo[1,5-a]pyridin-1-yl]methanesulfonamide

116 μl (1.49 mmol) of mesyl chloride are added, under a nitrogenatmosphere at a temperature of 5° C., to 0.473 g (1.36 mmol) of(1-aminoimidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitrophenyl)methanonehydrochloride obtained in example 76 in 14 ml of pyridine. On completionof the introduction, the mixture is allowed to return to ambienttemperature and is stirred for 30 minutes. The reaction medium is pouredunder 95 ml of 2N hydrochloric acid and extracted with ethyl acetate.The organic phase is washed with water, separated by settling, driedover sodium sulfate and concentrated under reduced pressure. The solidresidue obtained is taken up in isopropyl ether, filtered off, washedwith isopropyl ether and then dried. 0.40 g of an orange solid iscollected. Melting point: 231° C.; ¹H NMR (d₆-DMSO): 3.24 (3H, s), 4.02(3H, s), 7.40-7.44 (1H, m), 7.49-7.53 (1H, m), 7.88-7.92 (1H, d),8.00-8.07 (2H, m), 8.26 (1H, s), 9.75 (1H, d)

Example 81(4-Amino-3-methoxyphenyl)[1-(4-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl]methanone

0.167 g of 10% Pd/C and then 2.1 ml (21 mmol) of cyclohexene are addedto 0.835 g (2.07 mmol) of(3-methoxy-4-nitrophenyl)[1-(4-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl]methanoneobtained in example 25 in 30 ml of dioxane and 10 ml of ethanol and themixture is heated at reflux for 7 hours. The reaction medium is cooledand filtered through talc. The filtrate is concentrated under reducedpressure. The product is purified by column chromatography on silicagel, elution being carried out with a toluene/ethyl acetate (97/3)mixture. 0.760 g of a yellow solid is obtained. The product is salifiedby dissolution of the powder obtained above in acetone and then additionof 3.8 ml (2.6 equivalents) of 1N hydrochloric acid in ethyl ether.After addition of ethyl ether, the precipitate obtained is filtered off,washed with ethyl ether and then dried. 0.553 g of a yellow solid iscollected in the hydrochloride form. Melting point: 232° C.; ¹H NMR(d₆-DMSO): 3.85 (3H, s), 3.94 (3H, s), 6.95 (1H, d), 7.10-7.26 (3H, m),7.36-7.40 (1H, m), 7.96 (2H, d), 7.98-8.25 (3H, m), 9.76 (1H, d)

Examples 82 to 95

By carrying out the operation according to the preparation described inexample 81, the compounds of general formula Id described in table VIbelow are synthesized by reduction of the nitrofunctional group of thecompounds of formula Ia with cyclohexene in the presence of 10% Pd/C ascatalyst.

TABLE VI Melting point Ex. R R₁ R₂ R₃ Salt (° C.) 82 H H CO₂Me NH₂ — 19583 6-CO₂Me H OMe NH₂ — 179 84 6-CONH₂ H OMe NH₂ HCl•0.4H₂O 224 85 H CNOMe NH₂ HCl 224 86 H NHCOCH₃ OMe NH₂ HCl•0.4H₂O 237 87 7-CONHCH₂CO₂Et HOMe NH₂ HCl 219 88 (R)-7- H OMe NH₂ HCl•1.42H₂O 192 CONHCH(CH₃)CO₂Me 89(S)-7- H OMe NH₂ HCl•0.65H₂O 190 CONHCH(CH₃)CO₂Me 90 6-CONHCH₂CO₂Me HOMe NH₂ HCl•0.3H₂O 190 91 (S)-6-CONHCH(Bn)CO₂Me H OMe NH₂ HCl•H₂O 230 926-CONHCH₂CH₂CO₂Me H OMe NH₂ HCl•H₂O 174 93 (S)-6-CONHCH(Me)CO₂Me H OMeNH₂ HCl 124 94 6-NHMe H CO₂Me NH₂ — 122 95 6-CONHMe H OMe NH₂HCl•1.05H₂O 256

The NMR data for examples 82 to 95 in table VI are presented in tableVI′ below:

TABLE VI′ Ex. ¹H NMR (d₆-DMSO) 82 3.87 (3H, s), 6.91 (1H, d), 7.19-7.22(1H, m), 7.30-7.36 (1H, m), 7.85 (1H, s), 7.96 (1H, d), 8.43 (1H, d),9.12 (1H, s), 9.69 (1H, d) 83 3.87 (3H, s), 3.94 (3H, s), 6.71 (1H, d),7.61 (1H, d), 7.89 (1H, s), 7.94-7.98 (2H, m), 8.25 (1H, d), 10.27 (1H,s) 84 3.89 (3H, s), 6.82 (1H, d), 7.65 (1H, d), 7.85 (1H, s), 7.94-7.98(2H, m), 8.21 (1H, d), 10.15 (1H, s) 85 3.88 (3H, s), 6.82 (1H, d),7.33-7.39 (1H, m), 7.61-7.68 (1H, m), 7.79 (1H, s), 8.08 (2H, d), 9.59(1H, d) 86 2.15 (3H, s), 3.90 (3H, s), 6.90 (1H, d), 7.15-7.28 (2H, m),7.85-7.91 (2H, m), 8.15 (1H, d), 9.67 (1H, d) 87 1.21-1.27 (3H, s), 3.89(3H, s), 4.05-4.08 (2H, d), 4.12-4.20 (2H, q), 6.76-9.65 (2H, m),7.49-8.24 (2H, m), 7.96 (1H, s), 8.04 (1H, s), 8.47 (1H, s), 9.25 (1H,t) 88 1.44-1.47 (3H, d), 3.68 (3H, s), 3.98 (3H, s), 4.51-4.57 (1H, m),6.75-9.65 (2H, m), 7.51-8.24 (2H, m), 7.97 (1H, s), 8.04 (1H, s), 8.51(1H, s), 9.08-9.10 (1H, d) 89 1.44-1.45 (3H, d), 3.73 (3H, s), 3.92 (3H,s), 4.53-4.56 (1H, m), 6.74-9.61 (2H, m), 7.50-8.22 (2H, m), 7.96 (1H,s), 8.03 (1H, s), 8.49 (1H, s), 9.05-9.08 (1H, d) 90 3.70 (3H, s), 3.89(3H, s), 4.09 (2H, d), 6.83 (1H, d), 7.64 (1H, d), 7.88 (1H, s),7.98-8.02 (2H, m), 8.22 (1H, d), 10.18 (1H, s) 91 3.09-3.27 (2H, m),3.68 (3H, s), 3.89 (3H, s), 4.69-4.78 (1H, m), 6.82 (1H, d), 7.19-7.37(5H, m), 7.56 (1H, d), 7.86 (1H, s), 7.95-7.99 (2H, m), 8.21 (1H, d),10.15 (1H, s), 10.12 (1H, s) 92 2.64 (2H, t), 3.55 (2H, m), 3.63 (3H,s), 3.88 (3H, s), 6.84 (1H, d), 7.61 (1H, d), 7.85 (1H, s), 7.93-7.98(2H, m), 8.22 (1H, d), 10.12 (1H, s) 93 1.44 (3H, d), 3.68 (3H, s), 3.88(3H, s), 4.49 (1H, q), 6.81 (1H, d), 7.64 (1H, d), 7.76 (1H, s),7.85-7.98 (2H, m), 8.22 (1H, d), 10.12 (1H, s) 94 2.75 (3H, d), 3.86(3H, s), 6.88 (1H, d), 6.97 (1H, d), 7.66 (1H, s), 7.72 (1H, d), 8.45(1H, d), 8.97 (1H, s), 9.11 (1H, s) 95 2.84 (3H, d), 3.89 (3H, s), 6.87(1H, d), 7.64 (1H, d), 7.86 (1H, s), 7.96-8.00 (2H, m), 8.21 (1H, d),10.15 (1H, s)

Example 96(4-Amino-3-methoxyphenyl)[1-(1H-pyrrol-2-yl)imidazo[1,5-a]pyridin-3-yl]methanone

1.78 ml of acetic acid and 0.209 g of iron are added to 0.480 g (0.001mol) of tert-butyl2-[3-(3-methoxy-4-nitrobenzoyl)imidazo[1,5-a]pyridin-1-yl]pyrrole-1-carboxylateobtained in example 38 in solution in a mixture of 13 ml of water and 7ml of ethanol. The reaction medium is heated at 70° C. for 7 hours, isthen allowed to return to ambient temperature, is poured onto a 1Naqueous sodium hydroxide solution and is extracted with dichloromethane.The organic phase is separated by settling, dried over sodium sulfateand then concentrated under reduced pressure. The product is purified bycolumn chromatography on silica gel, elution being carried out withtoluene and then a toluene/ethyl acetate (90/10) mixture. 200 mg of abrown oil are obtained, which oil is salified in the hydrochloride form.60 mg of a red solid are obtained. Melting point: 136° C.; ¹H NMR(d₆-DMSO): 3.91 (3H, s), 6.21 (1H, m), 6.68 (1H, m), 6.81 (1H, d), 6.90(1H, m), 7.17-7.33 (2H, m), 7.98 (1H, s), 8.15 (1H, d), 8.38 (1H, d),9.73 (1H, d)

Examples 97 to 119

By carrying out the operation according to the preparation described inexample 96, the compounds of general formula Id described in table VIIbelow are synthesized by reduction of the nitro functional group of thecompounds of formula Ia with iron and acetic acid.

TABLE VII Melting point Ex. R R₁ R₂ R₃ Salts (° C.) 97 H 3-chlorophenylOMe NH₂ 0.8HCl 230 98 H 4-chlorophenyl OMe NH₂ 0.7HCl 230 99 H4-fluorophenyl OMe NH₂ 1HCl•0.02H₂O 214 100 H 3-pyridinyl OMe NH₂1HCl•1.97H₂O 248 101 H 4-pyridinyl OMe NH₂ 1HCl•0.89H₂O 237 102 H Br OMeNH₂ 0.3HCl•0.15H₂O 204 103 8-CO₂Et H OMe NH₂ 1HCl•0.6H₂O 189 104 7-CO₂EtH OMe NH₂ HCl 220 105 H NHCOPh-3-OMe OMe NH₂ 0.7HCl•0.15H₂O 199 106 H—NHSO₂CH₃ OMe NH₂ 1HCl•0.95H₂O 226 107 H NH—Me OMe NH₂ 1.9HCl 210 108(S)-6- H OMe NH₂ 1HCl•1.2H₂O 179 CONHCH(CH₂OH)CO₂Me 109 6-NHSO₂CH₃ H OMeNH₂ 0.4HCl 125 110 6-NHCOCH₃ H OMe NH₂ HCl 228 111 H -Ph-3-CO₂Me OMe NH₂— 166 112 7-CO₂Et 4- OMe NH₂ — MH+ = 447 methoxypyridin- 3-yl 113 H4-fluorophenyl CO₂Me NH₂ — 234 114 H 3-fluoro-4- OMe NH₂ HCl•0.14H₂O 226methoxyphenyl 115 7-OBn H OMe NH₂ 1.2HCl•0.2H₂O 210 116 (S)-7- H OMe NH₂1.55HCl 209 CONHCH(CH₂OH)CO₂Me 117 H 3-fluorophenyl OMe NH₂ HCl•1.25H₂O228 118 H 4-chlorophenyl CO₂Me NH₂ — 268 119 8-OBn H OMe NH₂1.5HCl•0.1H₂O 174

The NMR data for examples 97 to 119 in table VII are resented in tableVII′ below:

TABLE VII′ Ex. ¹H NMR (d₆-DMSO) 97 3.92 (3H, s), 6.81 (1H, d), 7.22-7.58(4H, m), 7.99-8.31 (5H, m), 9.73 (1H, d) 98 6.81 (1H, d), 7.20-7.45 (2H,m), 7.57-7.61 (2H, m), 8.04-8.29 (5H, m), 9.73 (1H, d) 99 3.92 (3H, s),6.86 (1H, d), 7.23-7.42 (4H, m), 8.03-8.27 (5H, m), 9.75 (1H, d) 1003.92 (3H, s), 6.80 (1H, d), 7.28-7.56 (2H, m), 8.04-8.18 (2H, m), 8.21(1H, d), 8.44 (1H, d), 8.81 (1H, d), 9.05 (1H, d), 9.41 (1H, s), 9.74(1H, d) 101 3.91 (3H, s), 6.82 (1H, d), 7.37-7.75 (2H, m), 7.97 (1H, s),8.16 (1H, d), 8.57-8.62 (3H, m), 8.87 (2H, d), 9.71 (1H, d) 102 3.88(3H, s), 6.80 (1H, d), 7.25-7.28 (1H, m), 7.38-7.45 (1H, m), 7.76 (1H,d), 7.84 (1H, s), 8.12 (1H, d), 9.67 (1H, d) 103 1.42 (3H, t), 3.88 (3H,s), 4.45 (2H, q), 6.78 (1H, d), 7.25 (1H, t), 7.92 (1H, s), 7.99 (1H,d), 8.14-8.20 (2H, m), 9.82 (1H, d) 104 1.36 (3H, t), 3.86 (3H, s), 4.36(2H, s), 6.70 (1H, d), 7.45 (1H, d), 7.92 (1H, s), 8.20 (1H, d), 8.57(1H, s), 9.59 (1H, d) 105 3.86 (3H, s), 3.88 (3H, s), 6.80 (1H, d),7.18-7.31 (3H, m), 7.44-7.50 (1H, m), 7.65-7.69 (2H, m), 7.81 (1H, d),7.89 (1H, s), 8.22 (1H, d), 9.71 (1H, d) 106 3.24 (3H, s), 3.89 (3H, s),6.84 (1H, d), 7.18-7.23 (1H, m), 7.30-7.36 (1H, m), 7.89 (1H, d), 7.99(1H, d), 8.06 (1H, s), 9.66 (1H, d) 107 3.29 (3H, s), 4.19 (3H, s),7.41-7.57 (3H, m), 8.08-8.35 (2H, m), 8.36 (1H, s), 9.98 (1H, d) 1083.69 (3H, s), 3.84 (2H, m), 3.90 (3H, s), 4.56-4.63 (1H, m), 6.87 (1H,d), 7.73 (1H, d), 7.88 (1H, s), 7.97-8.02 (2H, m), 8.21 (1H, d), 10.18(1H, s) 109 3.09 (3H, s), 3.87 (3H, s), 6.78 (1H, d), 7.22 (1H, d), 7.81(1H, s), 7.92-7.94 (2H, m), 8.21 (1H, d), 9.80 (1H, s) 110 2.13 (3H, s),3.89 (3H, s), 6.88 (1H, d), 6.91 (1H, d), 7.77 (1H, s), 7.85 (1H, d),7.95 (1H, s), 8.11 (1H, d), 10.32 (1H, s) 111 (CDCl₃) 4.00 (3H, s), 4.05(3H, s), 6.82-7.06 (2H, m), 7.01-7.04 (1H, m), 7.29-7.63 (2H, m),7.58-8.05 (2H, m), 8.07-9.40 (2H, m), 8.33 (1H, s) 112 1.35-1.39 (3H,t), 3.89 (3H, s), 3.96 (3H, s), 4.38-4.40 (2H, q), 5.93 (2H, m),6.72-7.06 (2H, m), 7.46-8.29 (2H, m), 8.06 (1H, s), 8.21-9.62 (2H, m),8.53 (1H, m), 8.76 (1H, m) 113 3.89 (3H, s), 6.89-7.42 (2H, m),7.21-8.10 (2H, m), 7.35-8.27 (2H, m), 7.35-7.43 (4H, m), 8.39-9.84 (2H,m), 9.49 (1H, s) 114 3.93 (6H, m), 6.82-7.37 (2H, m), 7.21-7.40 (2H, m),7.78-8.19 (2H, m), 8.15 (1H, m), 8.24-9.75 (2H, m) 115 3.88 (3H, s),5.02 (2H, m), 5.25 (2H, s), 6.78-9.63 (2H, m), 6.95-8.20 (2H, m),7.39-7.55 (6H, m), 7.60 (1H, s), 7.96 (1H, s) 116 3.68 (3H, s),3.83-3.85 (2H, d), 3.88 (3H, s), 4.55-4.62 (1H, m), 5.20-5.41 (2H, m),6.77-9.65 (2H, m), 7.54-8.24 (2H, m), 8.04 (1H, s), 8.19 (1H, s), 8.56(1H, s), 8.96-8.99 (1H, d) 117 3.94 (3H, s), 5.35 (2H, m), 6.90-9.76(2H, m), 7.22-7.28 (2H, m), 7.41-7.60 (2H, m), 7.87-7.88 (2H, m),7.88-8.34 (2H, m), 8.14-8.19 (2H, m) 118 6.88-8.30 (2H, m), 7.22-7.45(2H, m), 7.55-8.01 (4H, m), 8.27-8.30 (2H, m), 9.29 (1H, s), 9.73 (1H,m) 119 3.88 (3H, s), 6.76-9.29 (2H, m), 7.03-7.09 (1H, t), 6.80-8.23(2H, m), 7.82 (1H, s), 7.92 (1H, s)

Example 120(4-Amino-3-methoxyphenyl)[1-(3-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl]methanone

0.117 g of 10% Pd/C and then 0.27 ml (5.47 mmol) of hydrazine hydrateare added to 0.441 g (1 mmol) of(3-methoxy-4-nitrophenyl)[1-(3-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl]methanoneobtained in example 34 in 10 ml of methanol. The mixture is heated at70° C. for 3 hours. The reaction medium is filtered through talc and thecatalyst is washed with methanol. The filtrate is concentrated underreduced pressure. The residue is taken up in dichloromethane and washingis carried out with a saturated aqueous sodium chloride solution andthen drying is carried out over sodium sulfate. After concentratingunder reduced pressure, the residue is purified by column chromatographyon silica gel, elution being carried out with dichloromethane. 0.354 gof a yellow foam is collected. The product is salified by addition of 1Nhydrochloric acid in ethyl ether. After addition of ethyl ether, theprecipitate is filtered off, washed with ethyl ether and then dried. Ayellow solid is collected in the hydrochloride form. Melting point: 210°C.; ¹H NMR (d₆-DMSO): 3.86 (3H, s), 3.92 (3H, s), 6.88 (1H, d), 6.99(1H, d), 7.22 (1H, t), 7.40-7.60 (5H, m), 8.14-8.27 (3H, m), 9.75 (1H,d)

Examples 121 to 148

By carrying out the operation according to the preparation described inexample 120, the compounds of general formula Id described in table VIIIbelow are synthesized by reduction of the nitro functional group of thecompounds of formula Ia with hydrazine hydrate in the presence of 10%Pd/C as catalyst.

TABLE VIII Melting point (° C.) or Ex. R R₁ R₂ R₃ Salts M.S. 121 H2-methoxyphenyl OMe NH₂ 1HCl•0.4H₂O 211 122 H phenyl OMe NH₂1.4HCl•0.4H₂O 195 123 H 2-(5-carboxy- OMe NH₂ Na 275 thienyl) 124 H3-furyl OMe NH₂ 1HCl•0.5H₂O 187 125 H 3-thienyl OMe NH₂ 1HCl•1.1H₂O 200126 H 2-thienyl OMe NH₂ 1.65HCl 221 127 H 3-carboxyphenyl OMe NH₂1Na•2.5H₂O 239 128 H 3-pyridinyl CO₂Me NH₂ — 234 129 H 2-thienyl CO₂MeNH₂ — 143 130 H 3-methoxyphenyl CO₂Me NH₂ — 179 131* H 3-thienyl CO₂HNH₂ 1.8Na•2.6H₂O 284 132 H 2-methoxyphenyl CO₂Me NH₂ — MH+ = 402 133 H HOMe NH₂ HCl•0.2H₂O 218 134 H 4-methoxy- OMe NH₂ HCl•0.66H₂O 205pyridin-3-yl 135 8-CONMe₂ H OMe NH₂ HCl•1.7H₂O 125 136 H 3-furyl CO₂MeNH₂ — MH+ = 362 137 7-CONHMe H OMe NH₂ HCl 249 138 7-CONH₂ H OMe NH₂ HCl252 139 7-CONMe₂ H OMe NH₂ HCl dec.360 140 7-CONHMe 3-carboxyphenyl OMeNH₂ Na dec.360 141 7-CO₂Et 3-methoxyphenyl OMe NH₂ — MH+ = 432 142 H4-carboxyphenyl OMe NH₂ HCl 257 143 H 4-methoxy- CO₂Me NH₂ — 204pyridin-3-yl 144 8-Me H OMe NH₂ HCl 221 145 7-OH H OMe NH₂ HCl 238 1468-CONHMe H OMe NH₂ HCl•1.1H₂O 243 147 8-OH H OMe NH₂ HCl•1.35H₂O 254 1487-Me H OMe NH₂ HCl 235 *Methyl ester at R₂ saponified during thehydrogenation

The NMR data for examples 121 to 148 in table VIII are presented intable VIII′ below:

TABLE VIII′ Ex. ¹H NMR (d₆-DMSO) or M.S. 121 3.85 (3H, s), 3.90 (3H, s),6.88 (1H, d), 7.09-7.44 (5H, m), 7.66 (1H, d), 7.77 (1H, d), 8.11 (1H,s), 8.15 (1H, d), 9.72 (1H, d) 122 3.93 (3H, s), 6.85 (1H, d), 7.23-7.58(5H, m), 8.03 (2H, d), 8.16-8.30 (3H, m), 9.75 (1H, d) 123 3.94 (3H, s),6.84 (1H, d), 7.25-7.53 (2H, m), 7.75-7.80 (2H, m), 8.07 (1H, d), 8.21(1H, s), 8.33 (1H, d), 9.72 (1H, d) 124 3.93 (3H, s), 6.88 (1H, d), 7.12(2H, m), 7.22-7.39 (2H, m), 7.85 (1H, s), 8.14-8.22 (3H, m), 8.44 (1H,s), 9.74 (1H, d) 125 3.92 (3H, s), 6.81 (1H, d), 7.22-7.41 (2H, m),7.72-7.81 (2H, m), 8.09 (1H, m), 8.17 (2H, m), 8.30 (1H, d), 9.75 (1H,d) 126 6.80 (1H, d), 7.22-7.44 (3H, m), 7.60 (1H, d), 7.72 (1H, d), 8.06(1H, m), 8.28-8.33 (2H, m), 9.74 (1H, d) 127 3.94 (3H, s), 6.75 (1H, d),7.20-7.47 (3H, m), 7.87-7.95 (2H, m), 8.16-8.22 (2H, m), 8.27 (1H, s),8.58 (1H, s), 9.75 (1H, d) 128 3.90 (3H, s), 6.92 (1H, d), 7.26-7.46(4H, m), 7.46-7.59 (1H, m), 8.33-8.58 (3H, m), 8.60 (1H, d), 9.29 (1H,s), 9.51 (1H, s), 9.76 (1H, d) 129 3.89 (3H, s), 6.81-7.60 (6H, m),8.20-8.43 (2H, m), 9.13 (1H, s), 9.75 (1H, m) 130 3.87 (3H, s), 3.89(3H, s), 6.91-6.94 (2H, m), 7.24-7.62 (5H, m), 8.27-8.40 (2H, d), 9.55(1H, d), 9.77 (1H, d) 131 6.59 (1H, d), 7.12-7.35 (2H, m), 7.70-7.73(1H, m), 7.82 (1H, d), 8.06 (1H, d), 8.24-8.32 (2H, m), 9.09 (1H, s),9.69 (1H, d) 132 MH+ = 402 133 3.90 (3H, s), 6.93 (1H, d), 7.16-7.21(1H, m), 7.29-7.35 (1H, m), 7.84 (1H, s), 7.96 (1H, d), 7.98 (1H, s),8.18 (1H, d), 9.68 (1H, d) 134 3.93 (3H, s), 3.95 (3H, s), 7.03 (1H, d),7.22-7.45 (4H, m), 8.13-8.35 (4H, m), 8.80 (1H, s), 9.76 (1H, d) 1353.91 (3H, s), 6.89 (1H, d), 7.21 (1H, t), 7.32 (1H, d), 7.70 (1H, s),7.95 (1H, s), 8.18 (1H, d), 9.66 (1H, d) 136 3.89 (3H, s), 7.12-7.64(5H, m), 7.86-7.89 (1H, m), 8.15-8.25 (1H, m), 8.43-8.46 (1H, m), 9.39(1H, s), 9.75 (1H, d) 137 2.84 (3H, d), 5.96 (2H, m), 6.79-7.53 (2H, m),7.96 (1H, s), 8.00 (1H, s), 8.19-9.63 (2H, m), 8.41 (1H, s), 8.76 (1H,m) 138 5.80 (2H, m), 6.73-7.54 (2H, m), 7.64 (1H, m), 7.96 (1H, s), 7.64(1H, s), 8.20-9.26 (2H, m), 8.45 (1H, s) 139 3.88 (3H, s), 5.51 (2H, m),6.76-7.17 (2H, m), 7.90 (1H, s), 7.94 (1H, s), 8.02 (1H, s), 8.19-P.64(2H, m) 140 2.86 (3H, d), 3.94 (3H, s), 5.89 (2H, s), 6.74-7.47 (2H, m),7.52-8.20 (2H, m), 7.90-7.99 (1H, m), 8.27 (1H, s), 8.58-9.71 (2H, m),8.91 (1H, m) 141 CDCl₃: 1.27-1.50 (3H, t), 3.95 (3H, s), 4.02 (3H, s),4.44-4.52 (2H, q), 6.79-7.62 (2H, m), 6.99-7.52 (2H, m), 7.29-7.53 (2H,m), 8.23 (1H, s), 8.40-9.80 (2H, m), 8.78 (1H, s) 142 3.94 (3H, s),6.88-8.20 (2H, m), 7.26-7.48 (2H, m), 8.08-8.20 (5H, m), 8.34-9.77 (2H,m) 143 CDCl₃: 3.98 (3H, s), 4.05 (3H, s), 6.30 (2H, m), 6.75-6.95 (2H,m), 7.05-7.29 (2H, m), 7.99-9.92 (2H, m), 8.26-8.64 (2H, m), 8.79 (1H,s), 9.51 (1H, s) 144 2.59 (3H, s), 3.89 (3H, s), 6.83-8.20 (2H, m),7.06-9.55 (2H, m), 7.10 (1H, m), 7.86 (1H, s), 7.95 (1H, s) 145 3.88(3H, s), 6.82-6.88 (2H, m), 7.05 (1H, m), 7.51 (1H, s), 7.95 (1H, s),8.12-9.65 (2H, m) 146 2.86-2.87 (3H, d), 3.89 (3H, s), 5.23-5.25 (2H,m), 6.83-9.75 (2H, m), 7.20-7.26 (1H, t), 7.67-8.21 (2H, m), 7.93 (1H,s), 8.10 (1H, s), 8.74-8.75 (1H, m) 147 3.91 (3H, m), 6.42 (2H, m),6.43-8.18 (2H, m), 6.98-7.07 (2H, m), 7.85 (1H, s), 7.96 (1H, s),9.24-9.27 (1H, m) 148 2.41 (3H, s), 3.89 (3H, s), 6.00 (2H, m),6.82-8.21 (2H, m), 7.02-9.62 (2H, m), 7.69-7.71 (2H, m), 7.96 (1H, m)

Example 1493-(4-Amino-3-methoxybenzoyl)imidazo[1,5-a]pyridine-1-carboxamide

4.4 ml (26.4 mmol) of 6N aqueous sodium hydroxide solution are added to0.5 g (1.7 mmol) of3-(4-amino-3-methoxybenzoyl)imidazo[1,5-a]pyridine-1-carbonitrileobtained in example 85 in 50 ml of ethanol under a nitrogen atmosphere.After heating at reflux for 2 hours, the reaction medium is concentratedunder reduced pressure. The residue obtained is washed with water, withacetone and with ethyl ether and then dried. 0.447 g of a yellow solidis collected. The product is salified by addition of a 1N solution ofhydrochloric acid in ethyl ether. 0.310 g of a yellow solid is obtained.Melting point: 241° C.; ¹H NMR (d₆-DMSO): 3.89 (3H, s), 6.74 (1H, d),7.24-7.27 (1H, m), 7.45-7.49 (1H, m), 7.88 (1H, s), 8.33 (1H, d), 8.42(1H, d), 9.65 (1H, d)

Example 150 Methyl3-(4-amino-3-methoxybenzoyl)imidazo[1,5-a]pyridine-1-carboxylate

0.61 g (2.09 mmol) of3-(4-amino-3-methoxybenzoyl)imidazo[1,5-a]pyridine-1-carbonitrileobtained in example 85 is added to 20 ml of a solution of methanolsaturated with hydrochloric acid at a temperature of 5° C. and then themixture is allowed to return to ambient temperature and stirred for 17hours. The reaction medium is concentrated under reduced pressure. Theresidue is taken up in 14 ml of a 1N aqueous hydrochloric acid solutionand then heated at 70° C. for 5 h. The reaction medium is basified withsodium bicarbonate and extracted with a mixture of ethyl acetate andtetrahydrofuran. The organic phase is washed with water, dried oversodium sulfate and concentrated under reduced pressure. The residueobtained is taken up in dichloromethane and then filtered through a bedof silica gel, elution being carried out with a dichloromethane/methanol(99.8/0.2) mixture. 0.3 g of a yellow foam is collected. Melting point:63° C.; ¹H NMR (d₆-DMSO): 3.87 (3H, s), 3.92 (3H, s), 6.73 (1H, d),7.27-7.32 (1H, m), 7.57-7.62 (1H, m), 7.91 (1H, s), 8.14 (1H, d), 8.30(1H, d), 9.62 (1H, d)

Example 1512-Amino-5-{[1-(3-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl]carbonyl}benzoicacid

4.05 ml (8.1 mmol) of a 2N aqueous sodium hydroxide solution are addedto 0.650 g (1.62 mmol) of methyl2-amino-5-{[1-(3-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl]carbonyl}benzoateobtained in example 130 in solution in 30 ml of dioxane. The reactionmedium is heated at 60° C. for 2 hours and is then allowed to return toambient temperature. The mixture is concentrated under reduced pressure.The residue is taken up in dichloromethane. The organic phase is washedwith a 1N aqueous hydrochloric acid solution, dried over sodium sulfateand then concentrated under reduced pressure. The residue is purified bycolumn chromatography on silica gel, elution being carried out with adichloromethane/methanol (99/1) mixture. The 167 mg of orange solidobtained are salified in the sodium salt.0.98H₂O form. Melting point:257° C.; ¹H NMR (d₆-DMSO): 3.89 (3H, s), 6.64 (1H, d), 6.95 (1H, d),7.14-7.40 (3H, m), 7.44-7.60 (2H, m), 8.22 (1H, d), 8.32 (1H, d), 9.12(1H, s), 9.69 (1H, d)

Examples 152 to 161

By carrying out the operation according to the preparation described inexample 151, the compounds of general formula Ie described in table IXbelow are synthesized by saponification of the ester functional grouppresent on the R₂ or R₃ substituents of the compounds of formula Ib.

TABLE IX Melting point (° C.) Ex. R R₁ R₂ R₃ Salt or M.S. 152 H2-methoxyphenyl CO₂H NH₂ Na•1.15H₂O 297 153 H 2-thienyl CO₂H NH₂Na•0.8H₂O 265 154 H 3-pyridinyl CO₂H NH₂ Na•2.5H₂O 300 155 H4-methoxyphenyl CO₂H NHCOPh — MH+ = 492 156 H H CO₂H NH₂ Na•0.55H₂O 366157 H 3-furyl CO₂H NH₂ Na•1.14H₂O 296 158 H 4-fluorophenyl CO₂H NH₂Na•2.4H₂O 305 159 H 4-methoxy- CO₂H NH₂ Na•1.47H₂O 292 pyridin-3-yl 160H 4-chlorophenyl CO₂H NH₂ Na•1.47H₂O 338 161 6-NHMe H CO₂H NH₂ Na•1.2H₂O270

The NMR data for examples 152 to 161 in table IX are presented in tableIX′ below:

TABLE IX′ Ex. ¹H NMR (d₆-DMSO) 152 3.85 (3H, s), 6.65 (1H, d), 7.10-7.25(4H, m), 7.3 (1H, t), 7.65-7.75 (2H, m), 8.30 (1H, d), 8.92 (1H, s),9.63 (1H, d) 153 6.76 (1H, d), 7.09-7.35 (3, m), 7.45 (1H, d), 7.66 (1H,d), 8.16 (1H, d), 8.43 (1H, d), 9.13 (1H, s), 9.72 (1H, d) 154 6.79 (1H,d), 7.23-7.56 (2H, m), 7.56-7.58 (1H, m), 8.31-8.42 (3H, m), 8.58-8.60(1H, m), 9.23-9.26 (2H, m), 9.73 (1H, d) 155 3.85 (3H, s), 7.12 (2H, d),7.15-7.30 (1H, m), 7.43-7.49 (1H, m), 7.60-7.65 (3H, m), 8.00 (2H, d),8.11 (2H, d), 8.28 (1H, d), 8.62 (1H, d), 8.87 (1H, d), 9.26 (1H, s),9.82 (1H, d) 156 6.59 (1H, d), 7.08-7.10 (1H, m), 7.11-7.25 (1H, m),7.76 (1H, s), 7.88 (1H, d), 8.24 (1H, d), 8.97 (1H, s), 9.63 (1H, d) 1576.68 (1H, d), 7.13-7.37 (3H, m), 7.85 (1H, s), 8.17 (1H, d), 8.36 (1H,d), 8.41 (1H, s), 9.19 (1H, s), 9.77 (1H, d) 158 6.60-7.39 (2H, m),7.16-7.39 (2H, m), 7.36 (1H, m), 8.03-8.33 (2H, m), 8.06 (1H, m),8.19-9.69 (2H, m), 9.01 (1H, s) 159 3.95 (3H, s), 6.60-7.01 (2H, m),7.16-7.34 (2H, m), 8.20-8.35 (2H, m), 8.20-9.70 (2H, m), 8.81 (1H, s),9.08 (1H, s) 160 6.61-8.04 (2H, m), 7.17-7.56 (2H, m), 7.56-8.01 (4H,m), 8.32-8.33 (1H, m), 9.04 (1H, s), 9.66-9.69 (1H, m) 161 2.74 (3H, d),6.58 (1H, d), 6.90 (1H, d), 7.61 (1H, s), 7.67 (1H, d), 8.24 (1H, d),8.98 (1H, d)

Example 1622-Amino-5-{[1-(4-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl]carbonyl}benzoicacid

1.2 g of sodium hydroxide pellets are added to 0.259 g (0.5 mmol) of2-benzoylamino-5-{[1-(4-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl]carbonyl}benzoicacid obtained in example 155 in solution in 25 ml of dioxane. Themixture is heated at reflux for 48 hours. The reaction medium is allowedto return to ambient temperature. The medium is taken up in dioxane andthen acidified with potassium hydrogensulfate. The precipitate formed isfiltered off, then rinsed with water and dried. 0.162 g of a yellowsolid is collected, which solid is salified in the sodium salt.1.15H₂Oform. Melting point: 296° C.; ¹H NMR (d₆-DMSO): 3.85 (3H, s), 6.63 (1H,d), 7.09-7.17 (3H, m), 7.28-7.35 (1H, m), 7.96 (2H, d), 8.17 (1H, d),8.34 (1H, d), 9.04 (1H, s), 9.69 (1H, d)

Example 1633-(4-Amino-3-methoxybenzoyl)imidazo[1,5-a]pyridine-1-carboxylic acid

1.67 ml (1.67 mmol) of a 1N aqueous sodium hydroxide solution are addedto 0.272 g (0.84 mmol) of methyl3-(4-amino-3-methoxybenzoyl)imidazo[1,5-a]pyridine-1-carboxylateobtained in example 150 in 12 ml of a mixture (1/1) of dioxane andmethanol. After heating at reflux for 2 hours, the reaction medium isconcentrated under reduced pressure. The residue is taken up in waterand then acidified with 0.239 g (1.7 mmol) of potassium hydrogensulfate.The precipitate formed is filtered off, washed with water and ethylether, and dried. 0.22 g of an orange solid is collected, which solid issalified in the sodium salt.2.55H₂O form. Melting point: 226° C.; ¹H NMR(d₆-DMSO): 3.86 (3H, s), 6.71 (1H, d), 7.06-7.11 (1H, m), 7.24-7.30 (1H,m), 7.89 (1H, s), 8.34 (1H, d), 8.59 (1H, d), 9.63 (1H, d)

Example 1643-(4-Amino-3-methoxybenzoyl)imidazo[1,5-a]pyridine-6-carboxylic acid

1.51 ml (1.51 mmol) of a 1N aqueous sodium hydroxide solution are addedto 300 mg (0.92 mmol) of methyl3-(4-amino-3-methoxybenzoyl)imidazo[1,5-a]pyridine-6-carboxylateobtained in example 83 in 15 ml of a mixture (5/5/5) of dioxane,dichloromethane and methanol. The reaction medium is stirred at ambienttemperature overnight and then concentrated under reduced pressure. Theresidue is dissolved in water, washing is carried out with ethyl acetateand then the aqueous phase is acidified with 1.5 ml of 1N hydrochloricacid. The precipitate formed is filtered off, washed with water and thendried. 346 mg of a yellow solid are collected, which solid is salifiedin the sodium salt.0.7H₂O form. Melting point: 306° C.; ¹H NMR(d₆-DMSO): 3.87 (3H, s), 6.72 (1H, d), 7.70-7.78 (3H, m), 7.96 (1H, s),8.18 (1H, d), 10.09 (1H, s)

Examples 165 to 181

By carrying out the operation according to the preparation described inexample 164, the compounds of general formula Id described in table Xbelow are synthesized by saponification of the ester functional grouppresent on the R substituent.

TABLE X Melting point Ex. R R₁ R₂ R₃ Salt (° C.) 165 8-CO₂H H OMe NH₂ Na259 166 7-CO₂H H OMe NH₂ 1.2HCl•0.95H₂O 268 167 7-CO₂H 3-OMe-Ph OMe NH₂Na•2.7H₂O 307 168 7-CO₂H 4-methoxy- OMe NH₂ Na 295 pyridin-3- yl 1697-CONHCH₂CO₂H H OMe NH₂ Na•1.9H₂O 287 170 7-OCH₂CO₂H H OMe NH₂Na•0.95H₂O 302 171 (R)-7-CONHCH(CH₃)CO₂H H OMe NH₂ Na•1.5H₂O 77 172(S)-7-CONHCH(CH₃)CO₂H H OMe NH₂ Na•2.7H₂O 261 173 8-OCH₂CO₂H H OMe NH₂Na•2H₂O 313 174 7-CO₂H H OMe NHSO₂Me Na•2H₂O 321 175 8-O(CH₂)₃—CO₂H HOMe NH₂ Na•1.6H₂O 199 176 (S)-7- H OMe NH₂ Na•2.2H₂O 244CONHCH(CH₂OH)CO₂H 177 6-CONHCH₂CO₂H H OMe NH₂ Na•1.5H₂O 202 178(S)-6-CONHCH(Bn)CO₂H H OMe NH₂ Na•1.2H₂O 268 179 6-CONHCH₂CH₂CO₂H H OMeNH₂ Na•2.5H₂O 271 180 (S)-6-CONHCH(Me)CO₂H H OMe NH₂ Na•2.35H₂O 221 181(S)-6- H OMe NH₂ Na•1H₂O 244 CONHCH(CH₂OH)CO₂H

The NMR data for examples 165 to 181 in table X are presented in tableX′ below:

TABLE X′ Ex. ¹H NMR (d₆-DMSO) 165 3.88 (3H, s), 6.70 (1H, d), 7.12 (1H,t), 7.65 (1H, d), 7.91 (1H, s), 8.20 (1H, d), 8.33 (1H, s), 9.70 (1H, d)166 3.87 (3H, s), 6.72 (1H, d), 7.46 (1H, d), 7.93-8.06 (2H, m), 8.21(1H, d), 8.53 (1H, s), 9.60 (1H, d) 167 3.87 (3H, s), 3.92 (3H, s), 5.79(2H, m), 6.74-7.54 (2H, m), 6.98-7.65 (2H, m), 7.47-7.62 (2H, m),8.14-9.66 (2H, m), 8.24 (1H, s), 8.51 (1H, s) 168 3.90 (3H, s), 3.95(3H, s), 5.77 (2H, m), 6.72-7.05 (2H, m), 7.60-8.21 (2H, m), 8.13 (1H,s), 8.24-9.61 (2H, m), 8.41 (1H, s), 8.74 (1H, s) 169 3.52-3.54 (2H, d),3.88 (3H, s), 5.84 (2H, m), 6.71-9.62 (2H, m), 7.45-8.24 (2H, m),7.96-7.97 (2H, m), 8.12-8.16 (1H, t), 8.41 (1H, s) 170 3.85 (3H, s),4.20 (2H, s), 5.62-5.64 (2H, s), 6.67-9.59 (2H, m), 6.82-8.18 (2H, m),6.93 (1H, m), 7.49 (1H, s), 7.95 (1H, s) 171 1.42-1.44 (3H, d), 3.87(3H, s), 4.40-4.50 (1H, m), 5.85 (2H, s), 6.70-9.63 (2H, m), 7.50-8.23(2H, m), 7.96 (1H, s), 8.02 (1H, s), 8.48 (1H, s), 8.91-8.94 (1H, d) 1721.17-1.21 (3H, d), 3.87-4.04 (4H, m), 5.72 (2H, s), 6.62-9.60 (2H, m),7.42-8.29 (2H, m), 7.95-7.97 (2H, m), 8.38-8.42 (1H, d), 8.84 (1H, s)173 3.87 (3H, s), 4.36 (2H, s), 5.76 (2H, s), 6.40 (1H, m), 6.69-8.26(2H, m), 6.96-7.02 (1H, t), 7.77 (1H, s), 7.92 (1H, m), 9.22 (1H, m) 1743.07 (3H, s), 3.92 (3H, s), 7.44-9.65 (2H, m), 7.65-8.13 (2H, m), 7.93(1H, s), 8.09 (1H, m), 8.31 (1H, m) 175 1.94-1.98 (2H, m), 2.02-2.08(2H, m), 3.85 (3H, s), 4.21-4.23 (2H, m), 5.76-5.78 (2H, m), 6.87-8.21(2H, m), 6.74 (1H, m), 6.99-7.02 (1H, t), 7.74 (1H, s), 7.89 (1H, s),8.21 (1H, m), 9.23 (1H, m) 176 3.44-3.51 (2H, m), 3.60-3.72 (2H, m),3.87 (3H, s), 3.97-4. (2H, m), 5.84 (2H, s), 5.90-5.92 (1H, m),6.70-9.63 (2H, m), 7.45-8.23 (2H, m), 7.96-7.98 (2H, m), 8.19-8.20 (1H,m) 177 3.56 (2H, d), 3.88 (3H, s), 6.73 (1H, d), 7.60 (1H, d), 7.83 (1H,s), 7.92-7.96 (2H, m), 8.24 (1H, d), 10.10 (1H, s) 178 3.04-3.27 (2H,m), 3.86 (3H, s), 4.19-4.22 (1H, m), 6.71 (1H, d), 7.10-7.19 (5H, m),7.44 (1H, d), 7.81 (1H, s), 7.89-7.94 (4H, m), 8.24 (1H, d), 10.05 (1H,s) 179 2.18 (2H, t), 3.42 (2H, m), 3.79 (3H, s), 6.71 (1H, d), 7.56 (1H,d), 7.83 (1H, s), 7.93-7.95 (2H, m), 8.23 (1H, d), 10.10 (1H, s) 1803.52-3.59 (1H, m), 3.68-3.74 (1H, m), 3.87 (3H, s), 4.04-4.11 (1H, m),6.72 (1H, d), 7.60 (1H, d), 7.84 (1H, s), 7.93-7.97 (2H, m), 10.12 (1H,s) 181 1.31 (3H, d), 3.87 (3H, s), 3.92 (1H, q), 6.71 (1H, d), 7.54 (1H,d), 7.74 (1H, s), 7.92-7.95 (2H, m), 8.24 (1H, d), 10.10 (1H, s)

Example 1823-(3-Methoxy-4-nitrobenzoyl)imidazo[1,5-a]pyridine-6-carboxylic acid

1.64 ml (1.64 mmol) of a 1N aqueous sodium hydroxide solution are addedto 530 mg (1.49 mmol) of methyl3-(3-methoxy-4-nitrobenzoyl)imidazo[1,5-a]pyridine-6-carboxylateobtained in example 4 in a mixture of 20 ml of dioxane and 10 ml ofmethanol. The reaction medium is heated at 60° C. for 3 hours and thenconcentrated under reduced pressure. The residue is taken up in waterand the aqueous phase obtained is washed with dichloromethane and thenneutralized by addition of 1.64 ml of 1N hydrochloric acid. Theprecipitate formed is filtered off, washed with water and then dried.405 mg of a yellow solid are collected. Melting point: 313° C.; ¹H NMR(d₆-DMSO): 4.01 (3H, s), 7.78 (1H, d), 7.98 (1H, s), 8.06-8.10 (3H, m),8.15 (1H, s), 10.28 (1H, s)

Examples 183 and 184

By carrying out the operation according to the preparation described inexample 182, the compounds of general formula It described in table XIbelow are synthesized by saponification of the ester functional grouppresent on the R substituent.

TABLE XI Melting point Ex. R R₁ R₂ R₃ Salt (° C.) 183 8-CO₂H H OMe NO₂Na 332 184 7-CO₂H H OMe NO₂ — >350

The NMR data for examples 183 and 184 in table XI are presented in tableXI′ below:

TABLE XI′ Ex. ¹H NMR (d₆-DMSO) 183 4.00 (3H, s), 7.32 (1H, t), 7.82 (1H,d), 8.03-8.08 (3H, m), 8.47 (1H, s), 9.75 (1H, d) 184 4.02 (3H, s), 7.75(1H, m), 7.78 (1H, s), 7.96 (2H, m), 8.14 (1H, s), 8.30 (1H, m), 9.67(1H, m)

Example 185(4-Amino-3-methoxyphenyl)(8-methoxyimidazo[1,5-a]pyridin-3-yl)methanone

0.79 g (2.43 mmol) of cesium carbonate and then 0.05 ml (0.84 mmol) ofmethyl iodide are added to 0.22 g (0.76 mmol) of(4-amino-3-methoxyphenyl)(8-hydroxyimidazo[1,5-a]pyridin-3-yl)methanoneobtained in example 147 in 5 ml of DMF. The reaction medium is stirredat ambient temperature for 4 hours. After addition of a saturated sodiumhydrogencarbonate solution, the reaction medium is extracted with ethylacetate. The organic phase obtained is dried over sodium sulfate andconcentrated under reduced pressure. The residue is purified by columnchromatography on silica gel, elution being carried out withdichloromethane. 0.2 g of an orange-yellow solid is collected. Meltingpoint: 229° C.; ¹H NMR (CDCl₃): 3.86 (3H, s), 4.01 (3H, s), 5.80 (2H,m), 6.69 (1H, m), 6.69-6.72 (1H, m), 7.03-7.09 (1H, t), 7.78 (1H, s),7.92 (1H, s), 8.24 (1H, m), 9.25-9.28 (1H, m)

Examples 186 to 189

By carrying out the operation according to the preparation described inexample 185, the compounds of general formula Iz′ described in table XIIbelow are synthesized by O-alkylation of the compounds of generalformula Iz in the presence of an alkaline carbonate and of thecorresponding halide.

TABLE XII Melting point Ex. R R₁ R₂ R₃ Salt (° C.) 186 7-OCH₂CO₂Et H OMeNH₂ HCl 187 187 8-OCH₂CO₂Et H OMe NH₂ HCl 216 188 8-O(CH₂)₃—CO₂Et H OMeNH₂ 0.9HCl 174 189 8-OCH₂CH₂NMe₂ H OMe NH₂ 2HCl•3.25H₂O 142

The NMR data for examples 186 to 189 in table XII are presented in tableXII′ below:

TABLE XII′ Ex. ¹H NMR (d₆-DMSO) 186 1.31-1.36 (3H, t), 4.28-4.35 (2H,q), 4.49 (2H, s), 6.74-9.69 (4H, m), 7.50 (2H, m), 7.94 (1H, s), 8.21(1H, m) 187 1.21-1.27 (3H, t), 3.89 (3H, s), 4.17-4.26 (2H, q),5.08-5.11 (2H, m), 6.69-8.22 (2H, m), 6.86-6.89 (1H, m), 7.03-7.09 (1H,t), 7.21 (2H, m), 7.82 (1H, s), 7.93 (1H, m), 9.28 (1H, m) 188 1.10-1.22(3H, t), 2.05-2.16 (2H, m), 2.53-2.59 (2H, m), 3.89 (3H, s), 4.05-4.13(2H, q), 4.24-4.29 (2H, t), 5.44 (2H, m), 6.72-8.21 (2H, m), 6.85-6.88(1H, m), 7.04-7.10 (1H, t), 7.79 (1H, s), 7.92 (1H, m), 9.25-9.28 (1H,m) 189 2.85-2.91 (6H, d), 3.63-3.64 (2H, m), 3.89 (3H, s), 4.47 (2H, m),4.61-4.76 (2H, m), 6.79-8.20 (2H, m), 6.84-6.88 (1H, m), 7.08-7.14 (1H,t), 7.95 (1H, m), 8.05 (1H, s), 9.29-9.32 (1H, m)

Example 190 Methyl3-(3-{3-methoxy-4-[(propylsulfonyl)amino]benzoyl}imidazo[1,5-a]pyridin-1-yl)benzoate

0.17 ml (1.5 mmol) of 1-propanesulfonyl chloride is added to 0.5 g (1.24mmol) of methyl3-[3-(4-amino-3-methoxybenzoyl)imidazo[1,5-a]pyridin-1-yl]benzoateobtained in example 111 in 6 ml of pyridine. The reaction medium isstirred at ambient temperature for 18 h and then concentrated underreduced pressure. The residue obtained is taken up in dichloromethane.The organic phase obtained is washed with water, dried over sodiumsulfate and concentrated under reduced pressure. The residue obtained ispurified by column chromatography on silica gel, elution being carriedout with dichloromethane. 0.34 g of a yellow oil is collected. MS+: 508;¹H NMR (d₆-DMSO): 0.96-1.01 (3H, t), 1.74-1.81 (2H, m), 3.16-3.19 (2H,m), 3.92 (3H, s), 4.00 (3H, s), 7.33-7.73 (2H, m), 7.38-7.51 (1H, m),7.53-7.96 (2H, m), 8.03-8.30 (2H, m), 8.33-9.85 (2H, m), 8.38 (1H, s),8.63 (1H, s), 9.25 (1H, m)

Examples 191 to 194

By carrying out the operation according to the preparation described inexample 190, the compounds of general formula Ig described in table XIIIbelow are synthesized by sulfonylation or acylation of the compounds ofgeneral formula Id.

TABLE XIII Melting point Ex. R R₁ R₂ R₃ (° C.) 191 H Phenyl-3-CO₂Et OMeNHCOCH₂CH₃ MH+ = 458 192 H H OMe NHSO₂Me  78 193 7-CO₂Et H OMe NHSO₂Me187 194 H Br OMe NHSO₂Me 206

The NMR data for examples 191 to 194 in table XIII are presented intable XIII′ below:

TABLE XIII′ Ex. ¹H NMR (d₆-DMSO) 191 (CDCl₃): 1.24-1.29 (3H, t),2.43-2.50 (2H, m), 3.91 (3H, s), 3.96 (3H, s), 6.28-7.18 (2H, m),7.40-7.46 (1H, m), 7.88-8.02 (4H, m), 8.20-9.75 (2H, m), 8.32 (1H, s),8.45-8.55 (2H, m) 192 3.12 (3H, s), 3.94 (3H, s), 7.4-7.42 (2H, m),7.48-8.03 (2H, m), 7.90 (1H, s), 8.00-8.03 (2H, m), 8.14-9.73 (2H, m)193 1.35-1.40 (3H, t), 3.12 (3H, s), 3.93 (3H, s), 4.35-4.43 (2H, q),7.49-8.15 (2H, m), 7.56-9.66 (2H, m), 8.02 (1H, s), 8.10 (1H, s), 8.64(1H, s), 9.26 (1H, s) 194 3.12 (3H, s), 7.34-7.56 (2H, m), 7.53-7.56(1H, m), 7.84-7.85 (1H, m), 7.88 (1H, s), 7.91-7.92 (1H, m), 9.26 (1H,s), 9.72-9.73 (1H, m)

Example 1953-(3-{3-Methoxy-4-[(propylsulfonyl)amino]benzoyl}-imidazo[1,5-a]pyridin-1-yl)benzoicacid

1.4 ml of a 1N aqueous sodium hydroxide solution are added to 0.34 g(0.7 mmol) of methyl3-(3-{3-methoxy-4-[(propylsulfonyl)amino]benzoyl}imidazo[1,5-a]pyridin-1-yl)benzoateobtained in example 190 in 20 ml of methanol. The reaction medium isheated at 70° C. for 3 hours and then concentrated under reducedpressure. The residue is taken up in water and the aqueous phaseobtained is washed with dichloromethane, neutralized by addition of 1.4ml of 1N hydrochloric acid and then extracted with dichloromethane. Theorganic phase obtained is dried over sodium sulfate and concentratedunder reduced pressure. 0.19 g of a yellow solid is collected, whichsolid is salified in the sodium salt.2.1H₂O form. Melting point: 145°C.; ¹H NMR (d₆-DMSO): 0.96-1.01 (3H, t), 1.71-1.83 (2H, m), 3.16-3.19(2H, m), 4.00 (3H, s), 7.33-7.70 (2H, m), 7.36-7.38 (1H, m), 7.52-7.97(2H, m), 8.04-8.07 (2H, m), 8.27-9.85 (2H, m), 8.44 (1H, s), 8.64 (1H,s), 9.25 (1H, m)

Example 1963-{3-[3-Methoxy-4-[propionylamino]benzoyl]imidazo[1,5-a]pyridin-1-yl}benzoicacid

The compound is obtained by operating according to the preparationdescribed in example 195 by saponification of methyl3-{3-[3-methoxy-4-[propionylamino]benzoyl]-imidazo[1,5-a]pyridin-1-yl}benzoateobtained in example 191 with 1N sodium hydroxide solution. A yellowsolid is collected, which solid is salified in the sodium salt.2.4H₂Oform. Melting point: 145° C.; ¹H NMR (d₆-DMSO): 1.08-1.24 (3H, t),2.46-2.51 (2H, m), 4.03 (3H, s), 7.30-7.55 (3H, m), 7.88-8.38 (6H, m),8.43 (1H, m), 8.60 (1H, m), 9.40 (1H, m), 9.45 (1H, m), 9.95 (1H, m)

Example 197 Study of the ¹²⁵I-b-FGF Binding to the Purified Receptor FGFR α IIIc by the Proximity Scintillation Method

NBS plates (NBS plate 96 well solid white Corning 3600) are coated with100 μl of 0.1% gelatin per well, for 2 hours at 37° C. At the end of theincubation, the coating is removed and the plates are rinsed andthoroughly dried. 100 μl of binding buffer (40 mM Bis Tris buffer, pH7.0) are distributed into the plates.

Dilutions of the compounds of the invention are distributed into thewells in a proportion of 10 μl/well. 10 μl/well of b-FGF (Amersham ARM35050) and 10 μl/well of FGF R α III c (R&D Systems 658 FR) aresubsequently distributed. Afterwards, 10 μl/well of ¹²⁵I-b-FGF (DupontNEN NEX 268—specific activity>70 μCi) and 50 μl/well of SPA beads(Amersham RPQN 00019) are added. The plate is shaken for a few secondsand is incubated for 60 minutes at 37° C. with the exclusion of light.

At the end of the incubation, the plate is read in a Mibrobeta Triluxradioactivity counter (Wallac/PerkinElmer).

The compounds of the invention demonstrated a specific activity ofbetween 10⁻⁷ M and 10⁻⁹ M.

Example 198 Effects of the Compounds of the Formula I on theProliferation of HUVECs Versus 30 ng/ml of b-FGF or 10 ng/ml of a-FGF

24-well plates (Falcon Primaria) are coated with 200 μl of a fibronectinsolution (50 μg/ml, prepared in PBS)/well.

Inoculation is carried out in a proportion of 30 000 cells/ml/well in anRPMI 1640 medium+10% FCS+1% glutamine+heparin-ECGF (HE) mixture.

Incubation is carried out at 37° C., 5% CO₂, the time required for thecells to adhere.

The products are dissolved and solutions in DMSO/reaction medium havinga final concentration of 1 μM final to 10⁻⁷ M are prepared.

After adhesion of the cells at 37° C. for 6 hours in the presence of 5%CO₂, the medium is replaced with RPMI 1640 0.1% FCS+glutamine+HE.

For the derivatization, use is made, as negative control, of 0.1% FCS,as positive control, of 0% FCS and, as control, of 0.1% FCS+30 ng/ml ofb-FGF or 10 ng/ml of a-FGF. Incubation is subsequently carried out at37° C. for 24 hours in the presence of 5% CO₂.

On the second day, the cells are rinsed with 1 ml of PBS and 200 μl oftrypsin and then they are recovered in Isoton. Counting is carried out(n>9 μm).

In this test on proliferation of endothelial cells induced by b-FGF ora-FGF, the compounds of the invention demonstrated a specific activityof between 10⁻⁵ M and 10⁻⁹ M.

Example 199 Model of Angiogenesis In vitro

The gels are prepared by distributing, into each chamberslide well(Biocoat Cellware rat tail collagen, type I, 8-well culturesides: BectonDickinson 354630), 160 μl of matrigel diluted 1/6 (growth factor reducedMatrigel: Becton Dickinson 356230) in collagen (Rat Tail Collagen, typeI: Becton Dickinson 354236). Gelling is allowed to take place at 37° C.for 1 hour.

Human vein endothelial cells (HUVEC ref: C-015-10C, Cascade Biologics,Inc.) or porcine aortic endothelial cells (PAEC) are inoculated at15×10³ cell/well in 400 μl of EBM medium (Clonetics C3121)+2% FBS+hEGF10 μg/ml for the HUVECs and DMEM+3% FCS+2 mM glutamine+1 mM sodiumpyruvate+1% nonessential amino acids (GIBCO) for the PAECs.

Stimulation is carried out with b-FGF (TEBU/Peprotech) 10 ng/ml or a-FGF(TEBU/Peprotech) 10 ng/ml in the presence or absence of the products ofthe invention at 37° C. for 24 h in the presence of 5% CO₂.

After 24 hours, the cells are fixed and the slide is stained withMasson's trichrome before observation under a microscope, lens ×4, andimage analysis (Biocom, Visiolab 2000 software).

For the test for angiogenesis in vitro induced by b-FGF or a-FGF, thecompounds of the invention demonstrated a specific activity of between10⁻⁷ M and 10⁻¹¹ M.

Example 200 Model of Inflammatory Angiogenesis in the Mouse

Angiogenesis is required for the development of chronic inflammatorydiseases, such as rheumatoid arthritis or IBD, but also for thedevelopment of solid tumors. The formation of new vessels makes possiblenot only the perfusion of pathological tissues but also thetransportation of cytokines responsible for establishing the chronicityof the disease.

The model described by Colville-Nash P. et al. (D. JPET., 1995, Vol.274, No. 3, pp. 1463-1472) makes it possible to study pharmacologicalagents capable of modulating the appearance of angiogenesis.

The animals, nonconsanguineous white mice weighing approximately 25 g,are anesthetized with sodium pentobarbital (60 mg/kg; Sanofi NutritionSanté Animale) by the intraperitoneal route.

An air pouch is created on the back of the mouse by injecting 3 ml ofair subcutaneously.

After waking up, the animals receive a treatment, generally by forcefeeding, and receive an injection of 0.5 ml of Freund's adjuvant (Sigma)with 0.1% croton oil (Sigma) into the pouch.

Seven days later, the mice are again anesthetized and placed on aheating plate at 40° C. One ml of carmine red (5% in 10% gelatin,Aldrich Chemicals) is injected into the tail vein. The animals aresubsequently placed at 4° C. for 2-3 hours.

The skins are subsequently removed and dried in an oven at 56° C. for 48hours. The dried tissues are weighed and placed in 1.8 ml of digestionbuffer (2 mM dithiothreitol, 20 mM Na₂HPO₄, 1 mM EDTA, 12 U/ml papain)for 24 hours.

The stain is then dissolved in 0.2 ml of 5M NaOH. The skins arecentrifuged at 2000 g for 10 min. The supernatants are filtered through0.2 μm cellulose acetate membranes. The filtrates are read in aspectrophotometer at 492 nm against a carmine red calibration series.

Two parameters are studied: the dry weight of the granuloma and theamount of stain after digestion of the tissues.

The results are expressed as mean values (±SEM). The differences betweenthe groups are tested with an ANOVA followed by a Dunnett's test forwhich the reference group is the “solvent control” group.

The compounds of the invention are active by the oral route at doses of0.1 to 30 mg/kg.

Example 201 Model of Matrigel Angiogenesis in the Mouse

The model described by Passaniti et al. (Laboratory Investigation,(1992) 67(4), pp. 519-524) makes it possible to study pharmacologicalagents capable of modulating the appearance of the angiogenesisspecifically induced by b-FGF. FGF2 (Peprotech) is added, in aproportion of 300 ng/ml, to Matrigel (Beckton Dickinson) maintained inthe liquid form at 4° C. After homogenization, the mixture (0.5 ml) isinjected subcutaneously into the base of the back of female black mice(C57/B16) weighing approximately 20 g anesthetized beforehand withsodium pentobarbital (60 mg/kg; Sanofi Nutrition Santé Animale)intraperitoneally. The animals are treated by force feeding. After 5days, the mice are again anesthetized and the skin of the base of theback is removed; at this stage, the qualitative differences invascularization of the granuloma are evaluated (awarded scores) and thegranulomas are photographed. An assay of DNA in the granulomas issubsequently carried out in order to quantify its cellularity. For this,the isolated granulomas are digested with collagenase (3 mg/ml) at 37°C. overnight. After centrifuging at 850 g for 10 min, the supernatant isdiscarded and the pellet is redissolved in 1.2 ml of PBS buffercontaining 1 mM CaCl₂, 1 mM MgCl₂ and 5 mM glucose. The amount of DNApresent is measured using a kit (Cyquant-GR®, Molecular probe) accordingto the instructions of the supplier.

The results are expressed as mean values (±SEM). The differences betweenthe groups are tested with an ANOVA followed by a Dunnett's test forwhich the reference group is the “solvent control” group.

For the histological studies, the granulomas are removed with the muscleand the skin, fixed overnight in a 10% formaldehyde solution andembedded in paraffin (Embedder Leica®). The granulomas are subsequentlysliced using a microtome (Leica) and stained with Masson's trichromestain. The neovascularization of the granulomas is then evaluated. Thevascularization levels are between a value of 0 and a value of 5.

The compounds of the invention are active by the oral route at doses of0.1 to 30 mg/kg.

Example 202 Model of Tumor Angiogenesis in the Mouse

This model makes it possible to study pharmacological agents capable ofmodulating the appearance of the angiogenesis specifically induced bytumor development. C56/B16 mice weighing approximately 20 g areanesthetized with sodium pentobarbital (60 mg/kg; Sanofi Nutrition SantéAnimale) intraperitoneally. The tumors are established by subcutaneousinjection on the back of mouse Lewis lung cells in a proportion of 2×10⁵cells/mouse. After 5 days, the mice are treated daily by force feeding.The size of the tumors is measured twice weekly for 21 days and thetumor volume is calculated using the formula: [π/6(ω₁×ω₂×ω₂)], where ω₁represents the greatest diameter and ω₂ represents the smallestdiameter.

The results are expressed as mean values (±SEM). The differences betweenthe groups are tested with an ANOVA followed by a Dunnett's test forwhich the reference group is the “solvent control” group.

The compounds of the invention are active by the oral route at doses of0.1 to 30 mg/kg.

Example 203 Effect on Thrombopenia

Thrombopenia remains a pathology for which few effective treatmentsexist apart from the transfusion of platelet concentrates andthrombopoietin (Kaushansky, K., New Eng. J. Med., (1998), 339, pp.746-754).

Anticancer chemotherapy constitutes one of the major causes ofthrombopenia. One of the agents of chemotherapy, carboplatin, has beenwidely used to induce thrombopenia in the mouse and to be able thus tocharacterize the effect of compounds capable of improving the level ofplatelets, such as, for example, thrombopoietin (Hokom M. M. et al.,Blood, (1995), 86, pp. 4486-4492).

150 mg/kg of carboplatin were administered intraperitoneally to balbCmice having a weight of 20 g. A blood sample is taken periodically byretro-orbital puncture and the level of circulating platelets isdetermined by a hematology automated machine (MS9™ from Melet-SchloesingLaboratoires, Cergy-Pontoise, France). Under these conditions,reversible thrombopenia is observed with a nadir situated 9 to 10 daysafter the administration of carboplatin (reduction in the level ofcirculating platelets of 50-60%).

The compounds according to the invention or their solvent (ablank-control) are administered by the oral route for 5 days, thetreatment being begun 7 days before the administration of carboplatin.The experiments are carried out on batches comprising 10-12 mice and theresults are expressed as a mean ±standard error. Under these conditions,the compounds of the invention increase the level of circulatingplatelets at doses of 0.1 to 30 mg/kg.

Example 204 Model of CNV (Choroidal Neovascularization) Induced by anArgon Laser in the Mouse

A major characteristic of the loss of ocular transparency isneovascularization and the resulting hemorrhages, which cause majorfunctional disorders in the eye and which are effected by earlyblindness. Recently, the study of the mechanisms involved in thephenomena of ocular neovascularization has made it possible todemonstrate the involvement of proangiogenic factors in thesepathologies.

The model of laser-induced choroidal neoangiogenesis described by RakicJ. M. et al. in Invest. Opthalmol. Vis. Sci., (2003), Jul., 44(7), pp.3186-3193) makes it possible to study pharmacological agents capable ofmodulating the neovascularization of the choroid.

The mice are anesthetized by intraperitoneal injection of Avertin™. Thetwo pupils are dilated with a 1% tropicamide solution by topicalapplication, and three lesions are made around the optic disc using anargon laser (532 nm; spot size diameter 50 μm; duration 0.05 sec; 400mW). The optic disc is subsequently covered with a lens.

14 days later, the mice are sacrificed and the eyes are enucleated andfixed in a buffer containing 3.5% Formalin™, wrapped in TeK™ tissue(Miles Laboratories, Naperville, Ill.) and frozen in liquid nitrogen soas to be able to produce sections using a cryostat.

The choroidal neovascularization was quantified by a quantitativemorphometric study which makes it possible to evaluate the thickness ofthe network of neovessels present in the choroid using acomputer-assisted image analysis system (Olympus Micro Image version 3.0for Windows 95/NT, Olympus Optical Co. Europe GmBH).

Neovascularization is estimated by the ratio (B/C) of the thickness ofthe pigmented layer of the choroid in the lesion (B) to the thickness ofthis same pigmented layer in a region adjacent to the lesion (C). Theresults are expressed as mean values (±SEM). The differences between thetreated groups and the control groups are tested with an ANOVA followedby a Dunnett's test for which the reference group is the “controlsolvent” group.

The compounds of the invention are active by the oral route at doses of0.1 to 30 mg/kg.

1. A compound of formula I:

in which: R, present on the 5, 6, 7 or 8 positions of the imidazo[1,5-a]pyridine, represents a hydrogen atom, a halogen atom, an alkyl radical of 1 to 5 carbon atoms, a hydroxyl radical, an alkoxy radical of 1 to 5 carbon atoms, a —COOR₆ radical or a radical of formula: —NR₄R₅ —NH—SO₂-Alk —NH—CO-Alk —NR₆—CO₂-Alk —O-Alk-COOR₆ —O-Alk-NR₄R₅ —O—(CH₂)_(n)-Ph —CO—NR₄R₅, or —CO—NH—CH(R₇)—(CH₂)_(m)—COOR₆ in which: Alk represents an alkyl radical or an alkylene radical of 1 to 5 carbon atoms, n represents an integer from 1 to 5, m represents an integer from 0 to 4, R₄ and R₅ represent, independently of one another, a hydrogen atom, an alkyl radical of 1 to 5 carbon atoms or a benzyl radical, R₆ represents a hydrogen atom or an alkyl radical of 1 to 5 carbon atoms, R₇ represents a hydrogen atom, an alkyl radical of 1 to 5 carbon atoms or a radical of formula: -Alk-CONR₄R₅ -Alk-OR₆ -Alk-NR₄R₅ -Ph, or —CH₂Ph, and Ph represents a phenyl radical optionally substituted by one or more groups chosen from halogen atoms, alkoxy radicals of 1 to 5 carbon atoms and —COOR₆ radicals where R₆ is as defined above; R₁ represents a hydrogen atom, a halogen atom, a cyano radical, a —COOR₆ radical or a radical of formula: —NR₄R₅ —NH—SO₂-Alk —NH—CO—CF₃ —NH—CO-Ph —NH—CO-Alk —NH—CO₂-Alk —CONR₄R₅ a phenyl radical optionally substituted by one or more groups chosen from halogen atoms, alkyl radicals of 1 to 5 carbon atoms, alkoxy radicals of 1 to 5 carbon atoms and —COOR₆ radicals, a 5-membered heteroaryl radical comprising a heteroatom chosen from a sulfur atom, an oxygen atom or a nitrogen atom and optionally comprising a second nitrogen atom, said heteroaryl optionally being substituted by one or more groups chosen from halogen atoms, alkyl radicals of 1 to 5 carbon atoms, alkoxy radicals of 1 to 5 carbon atoms and —COOR₆ radicals, or a 6-membered heteroaryl radical comprising 1 or 2 nitrogen atoms and optionally being substituted by one or more groups chosen from halogen atoms, alkyl radicals of 1 to 5 carbon atoms, alkoxy radicals of 1 to 5 carbon atoms and —COOR₆ radicals, in which Alk, Ph, R₄, R₅ and R₆ are as defined as above; R₂ and R₃ represent, independently of one another, a hydroxyl radical, an alkoxy radical of 1 to 5 carbon atoms, an amino radical, a —COOR₆ radical, a nitro radical or a radical of formula: —NR₄R₅ —NH—CO-Alk —NH—CO-Ph —NH—CO₂-Alk —NH—SO₂-Alk —CO—NR₄R₅, or —CO—NHOH in which Alk, Ph, R₄, R₅ and R₆ are as defined as above; or else R₂ and R₃ together form, with the carbon atoms of the phenyl ring to which they are attached, a 6-membered carbon ring comprising a nitrogen atom and an oxygen heteroatom in the base or salt form.
 2. The compound of formula I as claimed in claim 1, in which: R, present on the 6, 7 or 8 positions of the imidazo[1,5-a]pyridine, represents a hydrogen atom, an alkyl radical of 1 to 5 carbon atoms, an alkoxy radical of 1 to 5 carbon atoms, a hydroxyl radical, a —COOR₆ radical or a radical of formula: —NR₄R₅ —NH—SO₂-Alk —NH—CO-Alk —NR₆—CO₂-Alk —O-Alk-COOR₆ —O-Alk-NR₄R₅ —O—CH₂-Ph —CO—NR₄R₅, or —CO—NH—CH(R₇)—(CH₂)_(m)—COOR₆ in which Alk, Ph, R₄, R₅, R₆, R₇ and m are as defined in claim 1; R₁ represents a hydrogen atom, a halogen atom, a cyano radical, a —COOR₆ radical or a radical of formula: —NR₄R₅ —NH—SO₂-Alk —NH—CO—CF₃ —NH—CO-Ph —NH—CO-Alk —CO—NR₄R₅ a phenyl radical optionally substituted by one or two groups chosen from halogen atoms, alkoxy radicals of 1 to 5 carbon atoms and —COOR₆ radicals; a 5-membered heteroaryl radical comprising a heteroatom chosen from a sulfur atom, an oxygen atom or a nitrogen atom and optionally comprising a second nitrogen atom, said heteroaryl optionally being substituted by one or two groups chosen from halogen atoms, alkyl radicals of 1 to 5 carbon atoms, alkoxy radicals of 1 to 5 carbon atoms and —COOR₆ radicals, or a 6-membered heteroaryl radical comprising 1 or 2 nitrogen atoms and optionally being substituted by one or two groups chosen from halogen atoms, alkyl radicals of 1 to 5 carbon atoms, alkoxy radicals of 1 to 5 carbon atoms and —COOR₆ radicals, where Alk, Ph and R₆ are as defined in claim 1; R₂ and R₃ represent, independently of one another, an alkoxy radical of 1 to 5 carbon atoms, a —COOR₆ radical, an amino radical, a nitro radical or a radical of formula: —NR₄R₅ —NH—CO-Alk —NH—CO-Ph —NH—SO₂-Alk in which Alk, Ph, R₄, R₅ and R₆ are as defined in claim 1; in the base or salt form.
 3. The compound of formula I as claimed in claim 2, in which: R, present on the 6, 7 or 8 positions of the imidazo[1,5-a]pyridine, represents a hydrogen atom, an alkoxy radical of 1 to 5 carbon atoms, a hydroxyl radical, a —COOR₆ radical or a radical of formula: —NR₄R₅ —NH—SO₂-Alk —NH—CO-Alk —NR₆—CO₂-Alk —O-Alk-COOR₆ —CO—NR₄R₅, or —CO—NH—CH(R₇)—(CH₂)_(m)—COOR₆ in which m represents 0 or 1, R₇ represents a hydrogen atom, an alkyl radical of 1 to 5 carbon atoms or a radical of formula -Alk-OR₆ or —CH₂-Ph, and Alk, R₄, R₅ and R₆ are as defined in claim 1; R₁ represents a hydrogen atom, a halogen atom, a cyano radical, a —COOR₆ radical or a radical of formula: —NR₄R₅ —NH—SO₂-Alk —NH—CO-Ph —NH—CO-Alk a phenyl radical optionally substituted by one or two groups chosen from halogen atoms, alkoxy radicals of 1 to 5 carbon atoms and —COOR₆ radicals, a heteroaryl radical chosen from thienyl, furyl and pyrrolyl radicals, said heteroaryl optionally being substituted by one or two groups chosen from alkoxy radicals of 1 to 5 carbon atoms and —COOR₆ radicals, or a pyridinyl radical optionally substituted by one or two groups chosen from alkoxy radicals of 1 to 5 carbon atoms and —COOR₆ radicals, R₂ and R₃ represent, independently of one another, an alkoxy radical of 1 to 5 carbon atoms, a —COOR₆ radical, a nitro radical, an amino radical or a radical of formula —NH—CO-Alk, —NH—CO-Ph or —NH—SO₂Alk; in the base or salt form.
 4. The compound of formula I as claimed in claim 1, in which R₂ represents an alkoxy radical of 1 to 5 carbon atoms or a —COOR₆ radical where R₆ is as defined in claim 1, in the base or salt form.
 5. The compound of formula I as claimed in claim 1, in which R₃ represents a nitro radical, an amino radical or a radical of formula NH—CO-Alk, —NH—CO-Ph or —NH—SO₂Alk, where Alk and Ph are as defined in claim 1, in the base or salt form.
 6. The compound of formula I as claimed in claim 1, in which: R, present on the 6, 7 or 8 positions of the imidazo[1,5-a]pyridine, represents a hydrogen atom, a hydroxyl radical, a —COOR₆ radical or a radical of formula: —O-Alk-COOR₆ —CO—NR₄R₅, or —CO—NH—CH(R₇)—COOR₆ in which R₇ represents a hydrogen atom, an alkyl radical of 1 to 5 carbon atoms or a radical of formula -Alk-OR₆ and Alk, R₄, R₅ and R₆ are as defined in claim 1; R₁ represents a hydrogen atom, a halogen atom, a —COOR₆ radical or a radical of formula: —NH—CO-Ph a phenyl radical optionally substituted by one or two groups chosen from halogen atoms, alkoxy radicals of 1 to 5 carbon atoms and —COOR₆ radicals or a thienyl radical optionally substituted by one or two groups chosen from alkoxy radicals of 1 to 5 carbon atoms and —COOR₆ radicals, in which Ph and R₆ are as defined in claim 1; R₂ represents an alkoxy radical of 1 to 5 carbon atoms or a —COOR₆ radical where R₆ is as defined in claim 1; and R₃ represents an amino radical, in the base or salt form.
 7. A process for the preparation of the compound according to claim 1, characterized in that: A) the compound of formula II:

in which R is as defined for the compound of formula I as claimed in claim 1 but R is other than a radical capable of reacting with the compound of formula III, selected from a hydroxyl radical, a carboxyl radical or an —NR₄R₅ radical, and R is other than an —NH—CO₂R₆ radical or a —CONR₄R₅ radical, is condensed with the compound of formula III:

in which X represents a halogen atom and R₂ and R₃ represent, independently of one another, an alkoxy radical of 1 to 5 carbon atoms, a nitro radical or a —COOR₆ radical in which R₆ represents an alkyl radical of 1 to 5 carbon atoms, in order to obtain: the compounds of formula Ia, which are compounds of formula I in which R₂ or R₃ represents a nitro radical, or the compounds of formula Ib, which are compounds of formula I in which R₂ or R₃ represents a —COOR₆ radical in which R₆ represents an alkyl radical of 1 to 5 carbon atoms, and, subsequently, a) the compounds of formula Ia are subjected to a reduction reaction, in order to obtain the compounds of formula Id:

in which R and R₁ are as defined for the compound of formula Ia and R₂ or R₃ represents an amino radical; the compounds of formula Id can subsequently be subjected to an alkylation, acylation or sulfonylation reaction in order to obtain the compounds of formula Ig:

in which R and R₁ are as defined for the compound of formula Id and R₂ or R₃ represents an —NR₄R₅ radical, an —NHCOAlk radical, an —NHCO₂Alk radical or an —NHSO₂Alk radical; b) or the compounds of formula lb are subjected to a saponification reaction in order to obtain the compounds of formula Ie:

in which R and R₁ are as defined for the compound of formula lb and R₂ or R₃ represents a carboxyl radical, the compounds of formula Ie can subsequently be subjected to a coupling reaction after activation of the carboxyl functional group, in the presence of a base, and then addition of an amine of formula HNR₄R₅ or of hydroxylamine in order to obtain the compounds of formula Ih:

in which R and R₁ are as defined for the compounds of formula Ie and R₂ or R₃ represents a —CONR₄R₅ or —CONHOH radical; OR B) the compound of formula II as defined above in part A) is condensed with the compound of formula III′:

in which X represents a halogen atom and R₂′ and R₃′ together form, with the carbon atoms of the phenyl ring to which they are attached, a 6-membered carbon ring comprising a nitrogen atom and another heteroatom, in order to obtain the compounds of formula Ic:

in which R and R₁ are as defined for the compound of formula II, said compounds of formula Ic subsequently being subjected to an alcoholysis reaction in order to give the compounds of formula If:

in which R and R₁ are as defined for the compound of formula II and R₆ is as defined for the compound of formula I, the compounds If can subsequently be saponified in order to obtain the compounds of formulae Id or Ie in which R and R₁ are as defined for the compound of formula II, R₂ represents a —COOH radical and R₃ represents an —NH₂ radical; OR C) the compound of formula I in which R₁ represents a hydrogen atom, as obtained above in part A), is subjected to a bromination reaction in order to obtain the compounds of formula Ii:

in which R, R₂ and R₃ are as defined for the compound of formula I as claimed in claim 1, when R₂ and R₃ do not together form a heteroaryl, and R₁ represents a bromine atom, the compounds of formula Ii for which R is other than a bromine atom or than an iodine atom can be subjected, in the presence of a palladium catalyst, of a ligand and of a base: a) either to an imination reaction with a benzophenone imine, followed by an acid hydrolysis reaction, in order to obtain the compounds of formula Ij:

in which R is as defined for the compounds Ii and R₂ and R₃ are as defined for the compound of formula Ii and R₁ represents an —NH₂ radical, b) or to a cyanation reaction with zinc cyanide in order to obtain the compounds of formula Ik:

in which R, R₂ and R₃ are as defined for the compounds Ii and R₁ represents a —CN radical, the compounds of formula Ik can subsequently be subjected to a basic hydrolysis reaction in order to obtain the compounds of formula Im:

in which R, R₂ and R₃ are as defined for the compounds of formula Ik and R₁ represents a —CONH₂ radical, or alternatively the compounds of formula Ik are subjected to a Pinner reaction with a primary alcohol in the presence of hydrogen chloride gas to result in the corresponding imidoester, which, by acid hydrolysis, results in the compounds of formula In:

in which R, R₂ and R₃ are as defined for the compounds of formula Ik and R₁ represents a —CO₂Alk radical where Alk is as defined in claim 1, it being possible for the compounds of formula In themselves to be subjected to a saponification reaction in order to obtain the compounds of formula Io:

in which R, R₂ and R₃ are as defined for the compounds of formula Ik and R₁ represents a —CO₂H radical, c) or to a Suzuki reaction with phenylboronic or heteroarylboronic derivatives in order to obtain the compounds of formula Is:

in which R, R₂ and R₃ are as defined for the compounds Ii and R₁ represents a substituted phenyl radical or an optionally substituted 5- or 6-membered heteroaryl; OR D) the compounds of formula Ij in which R₁ represents an amino radical are subjected to an acylation or sulfonylation reaction in order to obtain the compounds of formula Ip:

in which R, R₂ and R₃ are as defined for the compounds of formula Ij and R₁ represents an —NHCOAlk, —NHCO₂Alk, —NHSO₂Alk, —NHCOPh or —NHCOCF₃ radical in which Alk and Ph are as defined for the compound of formula I as claimed in claim 1, it being possible for the compounds of formula Ip in which R₁ represents an —NHCOCF₃ radical to be themselves subjected to an alkylation and then deprotection reaction, optionally followed by another alkylation reaction, in order to obtain the compounds of formula Iq:

in which R, R₂ and R₃ are as defined for the compounds of formula Ij and R₄ and R₅ are as defined for the compound of formula I; OR E) the compounds of formula Ir in which R represents a —CO₂R₆ radical where R₆ represents an Alk radical as obtained above in part A) are subjected to an acid or basic hydrolysis reaction in order to obtain the compounds of formula It:

in which R₁, R₂ and R₃ are as defined for the compound of formula Ir and R represents a —COOH radical, the compounds of formula It can subsequently be subjected: a) either to a coupling reaction after activation of the carboxyl functional group, in the presence of a base, and then addition of an amine of formula HNR₄R₅ or H₂N—CH(R₇)—(CH₂)_(m)—COOR₆ where R₆ represents an Alk radical as defined in claim 1, in order to obtain the compounds of formula Iu:

in which R₁, R₂ and R₃ are as defined for the compounds of formula It, and, when R is a —CONH—CH(R₇)—(CH₂)_(m)—COOR₆ radical where R₆ represents an Alk radical as defined in claim 1, these compounds can be saponified in order to obtain the compounds of formula Iu where R is a —CONN—CH(R₇)—(CH₂)_(m)—COOR₆ radical where R₆ represents a hydrogen atom and R₁, R₂ and R₃ are as defined above, b) or to Curtius rearrangements by the action of diphenylphosphoryl azide in the presence of triethylamine at reflux in an inert solvent and then addition of an alcohol of formula Alk-OH in order to obtain the compounds of formula Iv:

in which R₁, R₂ and R₃ are as defined for the compounds of formula It and R represents an —NHCO₂Alk radical, the compounds of formula Iv in which R represents an —NH—CO₂-Alk radical where Alk represents a -tBu radical can subsequently result in the compounds of formula Iw in which R₁, R₂, R₃, R₄ and R₅ are as defined for the compound of formula I as claimed in claim 1:

by deprotection in an acid medium, the compounds of formula Iw where R represents an —NH₂ radical are obtained, by alkylation followed by deprotection and by an optional second alkylation, the compounds of formula Iw where R represents an —NR₄R₅ radical can be obtained, the compounds of formula Iw where R represents an —NH₂ radical can be either acylated or sulfonylated in order to obtain the compounds of formula Ix:

in which R₁, R₂ and R₃ are as defined for the compound of formula Iw and R represents an —NHCOAlk or —NHSO₂Alk radical; OR F) the compounds of formula Iy:

in which R represents an —O-benzyl radical and R₁, R₂ and R₃ are as defined in the compounds of formula I as claimed in claim 1, are subjected to a debenzylation reaction in a protic solvent in the presence of palladium-on-charcoal in order to obtain the compounds of formula Iz:

in which R₁, R₂ and R₃ are as defined for the compounds of formula Iy and R represents a hydroxyl radical, and, when R₂ or R₃ represents a nitro functional group, the compounds of formula Id in which R₂ or R₃ represents an NH₂ radical and R₁ is as defined in the compounds of formula I are obtained, the compounds of formula Iz can subsequently be subjected to a selective O-alkylation reaction by the action at ambient temperature of an alkyl halide in a polar solvent in the presence of an alkaline carbonate in order to obtain the compounds of formula Iz′

in which R₁, R₂ and R₃ are as defined for the compounds of formula Iz, and, when R is an —O-Alk-COOR₆ radical where R₆ represents an Alk radical as defined for the compounds of formula I, these compounds can be saponified in order to obtain the compounds of formula Iz′ where R is an —O-Alk-COOR₆ radical where R₆ represents a hydrogen atom and R₁, R₂ and R₃ are as defined above.
 8. A pharmaceutical composition, comprising a compound according to claim 1 or a pharmaceutically acceptable salt, of this compound, and at least one pharmaceutically acceptable excipient. 